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Projections from the hippocampus, the mediodorsal thalamus (MD), and the ventral tegmental area (VTA) form interconnected neural circuits that converge in the prefrontal cortex (PFC) to participate in the regulation of executive functions. The present study assessed the roles that the MD and VTA play in regulating the hippocampal–PFC pathway using extracellular single-unit recordings in urethane-anesthetized rats. MD stimulation inhibited PFC neuron firing (∼100 msec duration) evoked by fimbria/fornix (FF) stimulation in a majority of neurons tested. However, this effect was reduced if activation of thalamocortical inputs occurred almost simultaneously (10 msec) with stimulation of the FF. In a separate population of neurons, burst stimulation of the MD produced a short-term (∼100 msec) inhibition or facilitation of FF-evoked firing in 66 and 33% of PFC neurons, respectively. Moreover, tetanic stimulation of the MD caused a longer-lasting (∼5 min) potentiation of FF-evoked firing. Burst stimulation of the VTA inhibited FF-evoked firing in a frequency-dependent manner: firing evoked by higher-frequency trains of pulses to the FF was less inhibited than firing evoked by single-pulse stimulation. The inhibitory actions of VTA stimulation were augmented by D1 receptor antagonism and attenuated by D2and D4 antagonists. Moreover, stimulation of the MD 10 msec before stimulation of the FF attenuated the VTA-mediated inhibition of evoked firing. Thus, both the MD and VTA exert a complex gating action over PFC neural activity, either facilitating or inhibiting firing in the hippocampal–PFC pathway depending on the frequency and relative timing of the arrival of afferent input.
- prefrontal cortex
- hippocampus
- ventral tegmental area
- mediodorsal thalamus
- dopamine
- in vivoelectrophysiology
- gating
- rat
Studies in both animals and humans have implicated the prefrontal cortex (PFC) and related subcortical afferent connections in mediating executive functions such as prospective coding, set-shifting, and working memory (Kolb, 1984;Hauser, 1999; Robbins, 1996; Goldman-Rakic, 1998; Miller, 2000). A contemporary theory of PFC function posits that the frontal lobes play an essential role in integrating different types of information, subserved by distinct cortical and subcortical networks, to organize behavior for the attainment of future goals (Miller, 2000; Fuster, 2001). Hippocampal projections to the PFC form one transcortical network that mediates cognitive processes such as working memory. In the rat, the ventral CA1/subicular region of the hippocampus sends glutamatergic projections to both pyramidal neurons and GABAergic interneurons of the prelimbic region of the PFC (Conde et al., 1995;Carr and Sesack, 1996; Gabbott et al., 2002). Stimulation of hippocampal afferents evokes excitatory and inhibitory responses in PFC neurons (Gigg et al., 1994; Jay et al., 1995, Mulder et al., 1997;Lewis and O'Donnell, 2000). The importance of hippocampal–PFC circuits in working memory is underscored by the finding that disconnection between these regions selectively disrupts retrieval of information during delayed responding (Floresco et al., 1997; Aujla and Beninger, 2001).
Two other subcortical nuclei that play a role in cognitive processes mediated by the hippocampal–PFC circuits include the ventral tegmental area (VTA) and the mediodorsal nucleus of the thalamus (MD). The VTA sends a dopaminergic projection to the PFC (Van Eden et al., 1987), and dopamine (DA) terminals are found often in close proximity to hippocampal terminals on PFC neurons (Carr and Sesack, 1996). Intracellular in vivo recordings have shown that stimulation of the VTA can produce a prolonged depolarization in PFC neurons accompanied by a reduction in spike firing (Lewis and O'Donnell, 2000). Moreover, VTA activation can exert two differential effects on hippocampal-evoked activity of PFC neurons: (1) an inhibition of firing evoked by low-frequency stimulation of the ventral subiculum and (2) an enhancement of long-term potentiation of the hippocampal–PFC pathway induced by high-frequency stimulation (Jay et al., 1995; Gurdren et al., 1999). These data suggest that DA input plays an important neuromodulatory role over activity in the hippocampal–PFC pathway, a contention supported by the findings that selective disruption of DA D1 receptor modulation of hippocampal inputs to the PFC impairs working memory mediated by hippocampal–PFC circuits (Seamans et al., 1998; Aujla and Beninger, 2001). The functional role of D2-like (D2, D4) receptors in the PFC remains to be established; however, activation of these receptors tends to inhibit PFC neural activity, either by direct actions on PFC pyramidal neurons or by facilitating GABAergic transmission (Sesack and Bunney, 1989;Rubinstein et al., 2001; Wedzony et al., 2001).
The MD shares a reciprocal glutamatergic projection with the PFC with thalamocortical inputs synapsing on layer III and V neurons, and possibly GABAergic interneurons as well (Krettek and Price, 1977;Groenewegen, 1988; Ray and Price, 1992; Pirot et al., 1994; Kuroda et al., 1998). Behavioral studies have implicated the MD in a broad range of PFC-related processes, including prospective coding (Joyce and Robbins, 1991; Daum and Ackermann, 1994) and strategy selection (Hunt and Aggleton, 1998). Of particular relevance is the fact that disconnection between the MD and PFC disrupts working memory processes dependent on both hippocampal–PFC circuits and mesocortical DA (Floresco et al., 1999).
The above-mentioned findings suggest that converging corticopetal inputs originating from the hippocampus, the MD, and the VTA may interact in a cooperative manner to regulate executive functions governed by the PFC. Despite this, it is surprising that there is a paucity of research investigating the mechanisms by which these inputs interact to influence PFC neural activity. As such, the present study was undertaken to assess the modulatory actions that inputs from the MD and the VTA exert over hippocampal-evoked firing of PFC neurons, usingin vivo extracellular single-unit recordings.
Materials and Methods
Subjects and surgery
Male Sprague Dawley rats (300–400 gm; Hilltop, Scottsdale, PA) were anesthetized with urethane (1.5 gm/kg, i.p.) and mounted in a stereotaxic frame, with the incisor bar set at −3.3 mm. Body temperature was maintained at 37°C with a temperature-controlled heating pad. In all surgical preparations, the scalp was incised and holes were drilled in the skull overlying the prelimbic region of the medial PFC, the fornix/fimbria (FF), the MD, and the VTA. Concentric bipolar electrical stimulating electrodes (SNE-100; Kopf, Tujunga, CA) were implanted into the three afferent regions of the PFC. The stereotaxic coordinates were as follows (flat skull): FF electrode = anteroposterior (AP) −1.3 mm (bregma), mediolateral (ML) +1.6 mm, dorsoventral (DV) −4.0 mm (cortex); MD electrode = AP −2.9 mm, ML +0.7 mm, DV −5.3 mm; VTA electrode = AP −5.4 mm, ML +0.7 mm, DV −7.8 mm. Animal care and surgical procedures were performed in accordance with the guidelines outlined in the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh.
Extracellular recordings and cell-searching procedures
Extracellular recording microelectrodes were constructed from 2.0 mm outer diameter borosilicate glass capillary tubing (WPI) using a vertical micropipette puller (Narishige, Tokyo, Japan). The tips of the electrodes were broken back against a glass rod to ∼1 μm tip diameter and filled with 2 m NaCl containing 2% Pontamine sky blue dye. Thein vitro impedance of the microelectrodes ranged from 5 to 10 MΩ as measured at 135 Hz using a Winston Electronics BL-1000 impedance meter. After a burr hole was drilled overlying the PFC, the dura was resected, and the electrode was lowered into the PFC (coordinates: +3.5–2.7 mm anterior from bregma, 0.6–0.8 mm lateral from the midline, 2.2–5.0 mm ventral from brain surface) with a hydraulic microdrive (Kopf Model 640). The electrode signal was amplified, filtered (400–4000 Hz), and discriminated from noise using a combination amplification and window discrimination unit for extracellular recording (Fintronics, Orange, CT) and displayed on an oscilloscope (Tektronics, Wilsonville, OR). The data were acquired, stored, and analyzed using custom-designed computer software (Neuroscope) running on an Intel-based personal computer with a data acquisition board interface (Microstar Laboratories, Bellevue, WA).
After the glass microelectrodes had been lowered to the dorsal border of the PFC, a cell-searching procedure began. In this procedure, the microelectrode was lowered incrementally through the PFC while alternating stimuli were delivered to the FF and the MD (1500 μA) at 1 sec intervals (i.e., each afferent was stimulated at 0.5 Hz). Although previous in vitro studies in hippocampus neurons have shown that prolonged low-frequency stimulation can induce long-term depression (Mulkey and Malenka, 1992), other studies in vivo have shown that extended bouts of low-frequency stimulation (1 Hz, 15 min) of the hippocampus does not produce any reliable change in synaptic efficacy in the PFC (Burette et al., 1997). Cathodal constant current pulses (0.2 msec duration) were delivered to the FF and MD through an Iso-Flex optical isolator (A.M.P.I., Jerusalem, Israel) via a Master-8 programmable pulse generator (A.M.P.I.) using the parameters noted below. Once a cell was detected, the position of the microelectrode was adjusted to maximize the spike amplitude relative to background noise. Neurons that responded only to FF stimulation or MD stimulation or received converging input from both regions were identified by their robust excitatory response after stimulation of the respective afferent region. Only neurons that responded with an orthodromic, monosynaptic response and displayed a signal-to-noise ratio of at least 3:1 were used in the data analysis. Evoked firing was characterized as monosynaptic/orthodromic if the response displayed spike jitter of at least 2 msec and a shift in spike latency with increasing current amplitude, followed by paired-pulse stimulation at 50 Hz (otherwise characterized as polysynaptic), but failed to follow 400 Hz paired-pulse stimulation (otherwise characterized at antidromic) (Pirot et al., 1994; Mulder et al., 1997).
With respect to MD-evoked responses, previous studies have demonstrated that electrical stimulation of the MD can evoke two types of monosynaptic responses in PFC neurons. Single-pulse stimulation can evoke a short latency (<10 msec) action potential that likely represents orthodromic activation of thalamocortical axons. However, higher-frequency (10 Hz) stimulation yields longer latency (>13 msec) spikes that are thought to be caused by antidromic activation of axons of PFC projection neurons that terminate in the MD but also have collaterals that synapse onto other PFC neurons (Pirot et al., 1994). Experiments assessing the conduction velocities of MD neurons projecting to the PFC have revealed that antidromically evoked firing of MD neurons occurs 2–11 msec after PFC stimulation (Pirot et al., 1994). In the present study, we observed that orthodromic monosynaptic action potentials evoked by single-pulse stimulation of the MD displayed a latency range of 6–22 msec (mean = 13.4 msec). However, to maximize the possibility that these responses were driven by activation of thalamocortical projections and not axon collaterals of PFC projection neurons, we included only PFC neurons that displayed MD-evoked orthodromic firing with latencies of ≤12 msec. Whenever a PFC neuron was encountered that displayed an antidromic spike after MD stimulation (but no response to FF stimulation), the location of that neuron was noted, but no other data were taken.
Stimulation protocols
After establishing that firing evoked by stimulation of the FF or MD was monosyaptic and orthodromic, stimulation currents were adjusted to submaximal stimulation intensity (range 100–1800 μA) so that stimulation of the FF or MD would evoke an action potential ∼60% of the time (range 40–75%, depending on the experiment) in response to single-pulse stimulation delivered at 0.2 Hz. In each of these experiments, data were compiled using a minimum of 25 sweeps. We used various stimulation protocols designed to investigate different types of interactions among hippocampal, MD, and VTA inputs to the PFC.
Interactions between converging inputs from the hippocampal and MD in the PFC: sequential-pulse protocols. In PFC neurons that displayed a monosynaptic orthodromic spike after stimulation of both the FF and MD, we conducted a series of sequential single-pulse stimulation experiments to assess how stimulation of one input could influence firing evoked by stimulation of the second input. In these experiments, each neuron received a conditioning pulse of one input followed by a test pulse of the other input, at intervals ranging between 10 and 500 msec, in a counterbalanced order, using the same stimulation intensity for each interstimulus interval (ISI). Paired-pulse facilitation/depression was also examined for each individual input, using 25–100 msec intervals between the conditioning pulse and the test pulse.
Modulation of hippocampal-evoked firing by burst stimulation of the MD. For some PFC neurons that only fired in response to FF and not MD stimulation, a series of experiments assessed the effect of burst stimulation of the MD on firing evoked by FF stimulation. In these studies, the stimulation intensity of the FF was adjusted so that the firing probability was ∼50% and kept constant throughout the course of the experiment. The firing probability was maintained at ∼50% so that we would be able to observe either inhibition or facilitation of FF-evoked firing by MD burst stimulation. After establishing baseline firing probabilities, we applied a four-pulse, 20 Hz train to the MD (800–1000 μA) 10, 25, or 50 msec before the FF pulse, with 25 sweeps collected for each interstimulus interval. This firing pattern mimics that displayed by MD neurons during learning (Oyoshi et al., 1996). Any neuron that displayed reliable firing in response to MD burst stimulation was not included in the data analysis. After each series of 25 sweeps, FF-evoked firing probability was monitored at the same stimulation intensity for 3–5 min using single pulses to the FF delivered at 0.2 Hz. This continued until the FF-evoked firing probability returned to ∼50%.
We also assessed effects of tetanic stimulation of the MD on longer lasting (i.e., minutes) changes of FF-evoked firing in PFC neurons. In this experiment, baseline probability of evoked firing in response to single pulses delivered to the FF were recorded over ∼10 min, using repeated sweeps administered every 2.5 min. Once stable levels of evoked-firing activity were observed (≤15% variation in spike probability over 5–10 min, three to four sweeps), 25 trains (four pulses, 20 Hz ISI) were delivered to the MD at a frequency of 0.2 Hz. Thirty seconds after this tetanus (assigned as time 0), the FF was again stimulated with single pulses at 0.2 Hz using the same stimulation current as before tetanus, and changes in FF-evoked firing probability were assessed for another 10 min with repeated sweeps recorded every 2.5 min. Data were normalized to the average firing probability observed over 5 min before tetanus and analyzed in terms of percentage change in firing probability. For both of the above-mentioned protocols, any neuron displaying reliable firing in response to MD burst stimulation was not included in the data analysis.
VTA modulation of FF-evoked firing of PFC neurons. For these experiments, FF stimulation intensities were adjusted to evoke an action potential ∼60–75% of the time after single-pulse stimulation of the FF delivered at 0.2 Hz. Once baseline firing probabilities were established, the VTA was stimulated in a burst pattern (two four-pulse 20 Hz trains of pulses; interburst interval = 200 msec) 10 or 50 msec before stimulation of the FF. Usually we stimulated the VTA with an intensity of 600 μA, but in some instances, the intensity was increased to up to 800 μA to induce a noticeable inhibition of FF-evoked firing. To assess whether activation of the VTA exerted a frequency-dependent modulation of evoked firing, we stimulated the FF first with single pulses and then with five-pulse, 20 Hz trains, each delivered at 0.2 Hz. The 20 Hz stimulation frequency mimics the way hippocampal projection neurons fire during working memory tasks (Hampson et al., 2000). We used a minimum of 25 sweeps per interburst interval to compile the data for all experiments assessing the effects of VTA stimulation.
Pharmacological manipulations
For some experiments involving burst stimulation of the VTA, separate groups of rats were implanted with intravenous jugular catheters, consisting of PE 10 tubing attached to a 30 ga needle and a 1 ml syringe. These experiments used a between-subjects design, and every animal received only one drug injection. After isolation of each PFC neuron, we confirmed that burst stimulation of the VTA inhibited hippocampal-evoked firing induced by single-pulse stimulation of the FF before drug administration. Baseline levels of FF-evoked firing were established, after which drugs were administered. We would then wait 10–20 min after drug injection before stimulating the VTA again. All drugs were purchased from Sigma (St. Louis, MO), with the exception of CP 293,019, which was donated by Pfizer (Groton, CT). The selective D1 receptor antagonist SCH23390 (0.2 mg/kg), the selective D2antagonist eticlopride (0.25 mg/kg), and the selective NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (2.0 mg/kg) were dissolved in physiological saline. The D2/D4 antagonist haloperidol (0.5 mg/kg) was dissolved in dilute lactic acid. The selective D4 antagonist CP 293,019 (10 mg/kg) was immersed in a drop of NaOH and 40% solution of cyclodextrin and sonicated until dissolved. The concentrations of these solutions were set so that injection volumes would range between 0.15 and 0.30 ml, and no more than one drug injection was given per animal. The doses of these drugs were chosen from previous studies (Gioanni et al., 1998;Mansbach et al., 1998; Floresco et al., 2001).
At the end of each experiment, the recording site in the PFC was marked via iontophoretic ejection of Pontamine sky blue dye from the tip of the recording electrode (30 μA constant current for 20–30 min). Iron deposits were made in the fimbria, the MD, and the VTA stimulation sites by passing DC current (100 μA for 10 sec) through the stimulating electrode. After dye ejection, brains were removed and fixed in formalin containing 0.1% potassium ferricyanide for at least 24 hr. The brains were then immersed in phosphate-buffered sucrose solution (25%) until saturated. The tissue was sectioned into 40 μm coronal slices, mounted, and stained with cresyl violet to enable histological determination of recording and stimulating electrode sites. Representative locations of different classes of PFC neurons and stimulating electrodes are presented in Figure 1.
Data analysis
The data were analyzed in terms of evoked firing probability in response to stimulation of the FF or MD, or percentage change of baseline-evoked firing probability. Evoked firing probabilities were calculated by dividing the number of action potentials observed by the number of stimuli administered (typically 25–50 pulses) × 100. For the sequential-pulse experiments that measured the interactions between hippocampal and MD inputs, the baseline firing probabilities evoked by each input were calculated by taking the mean firing probability evoked when that input was stimulated as the conditioning pulse. Changes in these probabilities were used as an index of the influence that MD or VTA inputs exerted over hippocampal-evoked firing of PFC neurons. The type of statistical analysis depended on the particular experiment, but typically entailed two- or three-way repeated measures ANOVA, with the exception of the pharmacological studies, which also included drug as a between-subjects factor. Multiple comparisons were made using two-tailed Dunnett's test for repeated measures.
General properties of PFC←Hipp neurons: convergence of inputs and projections to the MD and VTA
The data from a total of 114 PFC neurons that displayed a monosynaptic orthodromic spike after stimulation of the FF are presented here (hereafter referred to as PFC←Hipp neurons). These cells displayed a mean basal spontaneous firing rate of 3.1 ± 0.5 Hz (range 0.0–17.2 Hz; median firing rate 2.9 Hz) and had a mean evoked firing latency of 11 ± 0.8 msec (range 7–17 msec), consistent with previous findings (Mulder et al., 1997). Most of these 114 neurons that fired in response to FF stimulation were also tested for an antidromic response to MD or VTA stimulation. Ten of these cells (10 of 109; 9.2%) were confirmed PFC→MD projection neurons (mean antidromic spike latency = 11.2 ± 0.9 msec; range 7–18 msec), whereas 24.6% of these neurons (17 of 69) responded with an antidromic spike after VTA stimulation (mean antidromic spike latency = 9.6 ± 1.0 msec; range 4–19 msec). In addition, 4 of 60 neurons (6.7%) responded with an antidromic spike after stimulation of both the VTA and MD, suggesting that a subpopulation of PFC neurons that receive hippocampal input send axon collaterals to both regions (Fig. 1E). It is notable that many of the PFC←Hipp neurons were located in the same vertical electrode track where other PFC neurons that were antidromically activated by MD stimulation were observed. This suggests that most of the PFC←Hipp neurons that were recorded in the present study were located in the projection layers of the PFC. Last, and most pertinent to the present study, 13 of 105 PFC←Hipp neurons (12.4%) also displayed converging orthodromic input from the MD, exhibiting a monosynaptic action potential after MD stimulation that was within the latency range of our inclusion criterion (mean spike latency = 7.6 ± 0.6 msec). Representative locations of these neurons are shown in Figure 1. PFC←Hipp neurons that projected to the MD were clustered in the more rostral regions of the PFC and found in both prelimbic and infralimbic areas, whereas PFC←Hipp neurons that projected to the VTA clustered more rostrally and were located in the dorsal prelimbic region.
Interactions between converging hippocampal and MD inputs to the PFC
In six PFC neurons that displayed a monosynaptic spike in response to stimulation of both the FF and the MD (six rats), we administered a sequential-pulse stimulation protocol to assess how stimulation of one input could influence firing driven by the other input. In these cells, the basal firing probabilities evoked by either FF or MD single-pulse stimulation did not differ (FF = 55.7 ± 4/7%; MD = 53.6 ± 7.3%; F(1,5) = 0.04; NS). Application of a conditioning pulse to the FF 10–500 msec before a test pulse to the MD resulted in a profound and significant (p < 0.05) depression of MD evoked firing probability (Fig. 2A, black squares) compared with single-pulse stimulation of the MD alone (Fig. 2A, gray square) (F(6,30)= 3.5,p < 0.01; and Dunnett's, p < 0.05). The suppression of MD-evoked firing probability was maximal when the conditioning pulse to the FF was administered 10 msec before MD stimulation (−94 ± 3%), whereas longer intervals (25–500 msec) produced suppression of firing to between 45 and 75% of the baseline MD-evoked firing probability. In these same neurons, a similar profile was observed when a conditioning pulse was applied to the MD before a test pulse to the FF. In this instance, FF-evoked firing probability was significantly reduced by ∼60% when a conditioning pulse was administered 25–100 msec before FF stimulation (Fig.2B, black circles) when compared with single pulse of the FF alone (Fig. 2B, gray circle). However, application of a conditioning pulse to the MD either 10 or 250–500 msec before FF stimulation did not significantly effect the FF evoked firing probability (Fig. 2B, white circles) (F(6,30) = 5.6; p < 0.01). The duration of the inhibition of MD-evoked spiking by the FF was substantially longer (∼500 msec) than the reduction in FF-evoked firing mediated by the MD (∼100 msec). This difference may have been caused by differences in the duration of feed-forward inhibition evoked by each afferent. To investigate this difference further, we analyzed the duration of inhibition of spontaneous activity evoked by single-pulse stimulation of each afferent. In accordance with our findings using sequential-pulse protocols, single-pulse stimulation of the MD evoked an initial monosynaptic spike, which was followed by a period of inhibition of spontaneous firing that lasted 160 ± 21 msec. In contrast, inhibition of spontaneous firing evoked by FF stimulation had a substantially longer duration (403 ± 27 msec).
Subsequent analyses of these data were conducted to assess whether the neuron fired an action potential to the conditioning pulse to either MD or FF stimulation had any effect on the firing probability observed in response to the test pulse to the FF or the MD. Analysis of these data revealed that FF stimulation caused the same level of depression of MD-evoked spike firing independent of whether the FF conditioning pulse evoked a spike (F(1,5) = 0.2; NS). The reverse was also true: MD stimulation caused a similar depression in the response to FF stimulation independent of whether the MD condition pulse evoked an action potential (F(1,5) = 2.7; NS). Thus, activity in the hippocampal–PFC pathway 10–500 msec before impulse activity in the MD–PFC pathway can profoundly reduce the probability of firing induced by thalamocortical inputs, an effect that is not related to FF-evoked firing. The MD–PFC pathway exerts a similar gating action over hippocampal-evoked firing, although this inhibitory action occurs at a more temporally discrete range (25–100 msec). Importantly, the inhibitory influence that this thalamocortical pathway exerts over hippocampal-evoked firing of PFC neurons can be offset if impulse activity from the hippocampus arrives almost simultaneously with inputs from the MD (i.e., within ∼10 msec).
We also assessed paired-pulse facilitation/depression in the hippocampal–PFC or MD–PFC pathway individually, using 25, 50, and 100 msec interstimulus intervals between conditioning and test pulses (Table 1). For PFC←Hipp neurons (n = 10; six rats), delivering paired pulses to the FF at intervals of 50 or 100 msec, but not at 25 msec, resulted in significant paired-pulse facilitation (p < 0.01). In contrast, for neurons PFC←MD (n = 9; five rats), there was a significant (p < 0.05) paired-pulse depression of the test pulse at a 100 msec interval, but not at the 25 or 50 msec intervals (Fig. 2B) (F(2,34) = 6.9; p < 0.01).
Burst activation of the MD produces differential short-term gating of hippocampal-evoked firing in subpopulations of PFC neurons that are not activated by MD stimulation
In light of the dense thalamocortical projection to the PFC, we were surprised to observe that a relatively small proportion (<15%) of PFC←Hipp neurons fired a monosynaptic action potential after stimulation of the MD. However, this may be an underestimation of the total number of PFC←Hipp neurons that may be modulated by activity in the MD–PFC pathway. For example, it is possible that a greater proportion of PFC←Hipp neurons also received direct or indirect excitatory input from the MD, but the strength of these inputs was only sufficient to evoke a subthreshold EPSP unobservable using extracellular recordings. Alternatively, a proportion of MD axons may make connections with GABAergic interneurons in the PFC, which in turn synapse on PFC←Hipp neurons. With this in mind, we assessed how activation of the MD would affect hippocampal-evoked firing in PFC neurons that only displayed an extracellular spike after FF stimulation but not after MD stimulation.
Eighteen PFC←Hipp neurons that showed no reliable excitatory or inhibitory response to single-pulse MD stimulation were tested in this manner. In these cells, single-pulse stimulation of the MD 10–50 msec before a single pulse to the FF had no discernable effect over FF-evoked firing (Fig. 3C1). We then applied repeated four-pulse, 20 Hz train to the MD 10–50 msec before single-pulse stimulation of the FF. In all PFC neurons that were tested in this manner (n = 18; eight rats), burst stimulation of the MD had some effect over FF-evoked firing, revealing two distinct populations of PFC neurons. In 12 of these cells (67%), burst stimulation of the MD caused a pronounced reduction in the firing probability evoked by FF stimulation at all intervals tested, when compared with the firing probability observed after single-pulse stimulation of the FF alone (F(2,22) = 3.7, p < 0.05; and Dunnett's, p < 0.01) (Fig. 3A,C2). Four of these cells were tested further using intervals of 100 and 250 msec between the MD train and the single pulse to the FF. This protocol revealed that the inhibitory effects of MD stimulation were still apparent at intervals of 250 msec after an MD burst (data not shown). In contrast to the above-mention effects, in another six PFC←Hipp neurons (33%), burst stimulation of the MD had the opposite effect: an increased FF-evoked firing probability (F(1,5) = 6.92; p < 0.05) (Fig. 3B). The location of these two types of PFC neurons is shown in Figure 3D. We observed no consistent pattern of localization of these two types of neurons within the PFC; both types were found in the dorsal and ventral regions of the deep layers of the prelimbic and infralimbic cortex. Thus, these data imply that natural-type bursting activity in the thalamocortical pathway can exert differential gating actions on PFC neural activity driven by hippocampal inputs. Most PFC neurons are inhibited by bursting activity in the thalamocortical pathway, whereas another group of neurons displays a facilitation of hippocampal-evoked firing after MD burst stimulation.
Repeated burst stimulation of the MD produces a longer lasting potentiation of hippocampal-evoked firing in PFC neurons
Over the course of the above-mentioned series of experiments, we noticed an increase in the FF-evoked firing probability after repetitive burst stimulation of the MD (i.e., 25 bursts delivered at 0.2 Hz frequency), regardless of whether MD activation inhibited or facilitated FF-evoked firing, an effect that lasted a number of minutes. Therefore, we conducted another experiment to formally assess this heterosynaptic potentiation of FF-evoked firing by burst stimulation of the MD. Repeated burst stimulation of the MD resulted in a robust potentiation of FF-evoked firing probability in all neurons tested (n = 8; four rats) (Fig.4A,B1,B2). This potentiation of hippocampal evoked firing probability reached a peak at 1 min after tetanus (+46.7 ± 14%) (Fig.3B1,B2) and remained significantly elevated for another 6–8 min before returning to baseline levels of evoked firing probability (F(7,91) = 4.7,p < 0.01; and Dunnett's, p < 0.05, 0.01). To confirm that the potentiation of hippocampal-evoked firing was not merely caused by repetitive single-pulse stimulation of the FF, a separate group of neurons (n = 6; three rats) were tested under conditions in which the MD was not stimulated. These neurons displayed no significant change in the probability of firing evoked by repetitive single-pulse FF stimulations over a 15 min period (F(7,91) = 0.32, NS) (Fig.4A, gray circles). Thus, repetitive bursting activity in this thalamocortical pathway can produce a robust, short-term potentiation of hippocampal-evoked firing of PFC neurons, thereby priming PFC neurons to be more responsive to information conveyed by the hippocampus.
Interactions between hippocampal and VTA inputs to the PFC
Single-pulse stimulation of the FF
In a separate group of PFC←Hipp neurons, we assessed the effect of burst stimulation of the VTA on FF-evoked firing of PFC neurons. All of the neurons tested (n = 54; 51 rats) fired in response to FF stimulation but showed no monosynaptic response after MD stimulation. These data are presented in Figure5. In accordance with previous findings (Jay et al., 1995; Gurden et al., 1999), burst stimulation of the VTA produced a drastic inhibition of FF-evoked firing (F(1,22) = 80.0, p < 0.001; and Dunnett's, p < 0.01) (Fig. 5). This inhibitory effect of VTA stimulation was apparent when the interval between the last pulse in the VTA burst and the single stimulation of the FF was either 10 or 50 msec (F(1,22) = 8.7; p < 0.01). Others have shown that single-pulse stimulation of the VTA inhibits hippocampal-evoked activity only at intervals of <25 msec (Jay et al., 1995; Gurden et al., 1999). Thus, burst stimulation of the VTA, which is known to be more effective at releasing mesolimbic DA than single pulses (Garris and Wightman, 1994), inhibits firing of PFC neurons evoked by single-pulse stimulation of the hippocampus, and this effect lasts at least 50 msec after the end of the VTA burst.
Train stimulation (20 Hz) of the FF
A number of recent studies have shown that the actions of DA on evoked activity in PFC neurons are dependent on the frequency at which excitatory inputs are stimulated (Jay et al., 1995; Otani et al., 1998;Gurden et al., 1999; Seamans et al., 2001). In light of these data, we assessed the effect of burst stimulation of the VTA on hippocampal-evoked firing of PFC neurons when the FF was stimulated with a higher-frequency train of pulses. FF stimulation consisted of a five-pulse, 20 Hz train. Stimulation of the FF in this manner resulted in an equivalent probability of firing (75–90%) in PFC neurons throughout each pulse in the train (Figs.6A, gray circles, 7A1). However, activation of the VTA before 20 Hz train stimulation of the FF altered this firing profile in an interesting manner. Burst stimulation of the VTA produced a profound reduction in the firing probability observed after the first pulse in the five-pulse train delivered to the FF, when compared with the firing probability observed at the same time point when no VTA stimulation was given (75.8 ± 4 vs 7.4 ± 3%) (Fig.6A, gray square). However, the firing probability observed in the latter parts of the train was significantly less attenuated compared with the firing probability evoked by the first pulse (Figs. 6A, black squares, 7A2) (mean = 52.3 ± 7%; F(4,36)= 7.1; p < 0.01). This effect emerged by the second pulse in the train, and the firing probability evoked by pulses 2–5 did not differ throughout the course of the train. It is important to note that burst stimulation of the VTA still caused a significant reduction (p < 0.01) in the firing probability evoked by later pulses in the train compared with the firing probability at the same time points of the train when no VTA stimulation was administered, but the magnitude of this inhibition was substantially reduced compared with that observed during the first pulse (first pulse firing probability = 7.4 ± 3%; pulses 2–5 = 52.3 ± 7%; p < 0.01). From these data it is apparent that the inhibitory actions that the VTA exerts over hippocampal-evoked firing in PFC neurons are frequency dependent. Burst stimulation of the VTA can drastically inhibit firing evoked by single-pulse stimulation of the hippocampus. However, if impulse traffic in the hippocampal–PFC pathway occurs in the form of a higher-frequency train of action potentials, the VTA-mediated inhibition is reduced substantially in the latter portions of the train.
Selective DA receptor antagonists alter the effects of VTA stimulation on FF-evoked firing
To ascertain the role that DA receptors play in the effects of VTA stimulation, we administered selective DA receptor antagonists before burst stimulation of the VTA. Analysis of these data revealed significant drug × pulse number × VTA stimulation interaction (F(20,192) = 1.9;p < 0.05). Simple main effects analysis revealed that when no VTA stimulation was administered, there were no significant differences between drug treatment groups with respect to the firing probabilities evoked by train stimulation of the FF (F(5,48) = 0.1; NS). This finding indicates that any differences between the control condition and the drug treatment group could not be attributed to group differences in the firing probabilities evoked by train stimulation alone. Furthermore, the fact that blockade of D1, D2, or D4 receptors did not alter firing probabilities evoked by 20 Hz train stimulation implies that any increase in mesocortical DA release that may be caused by stimulation of hippocampal afferents (Gurden et al., 2000) does not influence spike firing evoked during train stimulation.
D1 receptor blockade
Administration of the D1 antagonist SCH 23390 (0.2 mg/kg, i.v.; n = 9) markedly enhanced the inhibitory actions of VTA stimulation on firing evoked by train stimulation of the FF (Figs. 6B, 7B). Burst stimulation of the VTA caused a pronounced inhibition of firing evoked by the second and third pulse of the five-pulse FF train. In fact, the firing probabilities at these time points did not differ from the firing probability evoked by first pulse (Fig.6B, white squares). Moreover, the firing probability at the middle portion of the train was significantly inhibited compared with the probability observed at the same time points for control neurons. The firing probability evoked by the last two pulses in the train was significantly reduced (p < 0.01) when compared with the firing probability at the same time points of the train when no VTA stimulation was administered but was significantly higher (p < 0.01) than the firing probability evoked by the first pulse of the train. Thus, D1receptor blockade revealed an underlying potent VTA-mediated inhibition during the latter parts of the train.
D2 receptor blockade
In contrast to the effects of D1 receptor blockade, intravenous administration of the D2receptor antagonist eticlopride (0.25 mg/kg; n = 10) abolished the inhibitory actions of VTA stimulation on firing evoked by the latter parts (pulses 3–5) of train stimulation of the FF but had no significant effect on the inhibition observed during the early parts of the train (Fig. 6C). This attenuation of the VTA-induced inhibition was even more pronounced after pretreatment with the D2/D4 antagonist haloperidol (0.5 mg/kg; n = 8). In these cases, VTA stimulation had no effect over the firing probabilities evoked by pulses 2–5, when compared with the probabilities observed when no VTA stimulation was given (Fig. 6D). Moreover, in the presence of haloperidol, VTA stimulation was less effective at inhibiting firing induced by the first pulse in the train, when compared with the control condition (p < 0.05).
D4 receptor blockade
Haloperidol has a higher affinity for DA D4receptors than eticlopride (Durcan et al., 1995; Seeman and Van Tol, 1995; Seeman et al., 1997) and was more effective than eticlopride in attenuating the inhibitory actions of VTA stimulation on FF-evoked activity. In addition, application of D4antagonists can increase the excitability of PFC neurons (Rubinstein et al., 2001). In keeping with these observations, administration of the selective DA D4 receptor antagonist CP 293,019 (10 mg/kg; n = 9) caused an effect like that of haloperidol but unlike that of eticlopride. D4receptor blockade attenuated significantly (p < 0.05) the VTA-induced inhibition of the firing probability evoked by the first pulse of the five-pulse FF train, when compared with neurons in the control condition (Fig. 6E). The effect of CP 293,019 on the firing probability evoked in the latter parts of the train were mixed; D4 receptor blockade appeared to reduce the VTA-induced inhibition of firing evoked by pulses 2–4, but the firing probability at these time points was still significantly lower when compared with the probabilities observed when no VTA stimulation was given. VTA stimulation did not affect the firing probability evoked by the fifth pulse in the train when compared with the same time point when no VTA stimulation was administered.
NMDA receptor blockade
Previous studies in vitro have shown that the facilitatory effects of D1 receptor activity on synaptic transmission in the PFC may be co-mediated by the NMDA receptor (Seamans et al., 2001). Therefore, we conducted an experiment to assess whether the frequency-dependent effects observed in the present study were mediated by NMDA receptors. Surprisingly, in eight cells tested, administration of the NMDA receptor antagonist CPP (2 mg/kg) caused no change in the firing probability evoked by train stimulation of the hippocampus after VTA stimulation (Fig.6F). As observed in the control condition, burst stimulation of the VTA drastically reduced the firing probability evoked by the first pulse in the train, whereas firing probability evoked by latter pulses in the train was significantly higher when compared with the first pulse. The discrepancy between the presentin vivo study and the effects reported by Seamans et al. (2001)in vitro may be attributed to a number of procedural differences, such as blockade of Na+channels in the study by Seamans and colleagues, the duration of the train used (5 vs 15 pulses), the dependent variable (spike firing vs subthreshold EPSPs), and method of DA receptor activation (VTA stimulation vs bath application of a selective D1receptor agonist).
The protocol used in the pharmacological experiments used between-subjects comparisons between animals that received injections of DA antagonists and those that received no drug treatment. However, as noted above, the effects of VTA stimulation on firing evoked by single-pulse stimulation of the FF was assessed for each individual cell, before any drug administration. Thus, we were able to conduct a within-subjects analysis of the effects of DA receptor blockade on the VTA-induced inhibition of firing evoked by single-pulse stimulation of the FF. Analysis of these data revealed that before drug administration, burst stimulation of the VTA drastically inhibited FF-evoked firing of all neurons in all groups [>80% reduction in firing probability (Fig. 8, gray bars) when compared with single-pulse stimulation alone (Fig. 8, white bar)]. Similar to the effects observed with train stimulation of the FF, the VTA-induced inhibition of firing evoked by single-pulse stimulation of the FF was not affected by SCH 23390 and was significantly (but not completely) attenuated by eticlopride, haloperidol, and CP 293,019 (F(4,32) = 3.0, p < 0.05; and Dunnett's, p < 0.05, p < 0.01) (Fig. 8, black bars). Thus, the finding that blockers for D2 and D4 receptors reduced the effects of burst stimulation of the VTA suggests that the inhibitory actions of VTA stimulation on evoked firing of PFC←Hipp neurons is mediated at least in part by the mesocortical DA projection.
To summarize, activation of the VTA exerts a frequency-dependent inhibition over firing driven by hippocampal inputs to the PFC. VTA stimulation potently inhibits hippocampal-evoked firing evoked by single-pulse stimulation. However, when this pathway is activated at a higher frequency, the inhibition of hippocampal-evoked firing is attenuated, and inputs from the temporal lobe are much more likely to evoke spike firing. The inhibitory actions of the VTA were reduced after blockade of DA D2 and D4 receptors. Moreover, the DA-mediated inhibition induced by stimulation of the VTA appears to have both an early and a late component. Inhibition that occurs <100 msec after the end of a VTA burst is reduced by D4 receptor blockade (CP 293,019) (Fig. 6E), whereas a later onset inhibition (100–250 msec after a VTA burst) appears to be mediated more prominently by D2 receptors (eticlopride) (Fig. 6C). Accordingly, treatment with an antagonist that has affinity for both D2 and D4 receptors (haloperidol) (Fig.6D) almost completely abolished the inhibitory actions of VTA stimulation. The finding that antagonists for both D2 and D4 receptors did alleviate much of the inhibitory actions of VTA stimulation implies that these effects are mediated primarily by DA and not the mesocortical GABA projection (Carr and Sesack, 2000). Last, blockade of D1 receptors disrupted the frequency-dependent modulation of impulse activity in this pathway, augmenting the VTA-mediated inhibition of FF-evoked firing.
Interactions among hippocampal, MD, and VTA inputs to the PFC
The above-mentioned findings indicate that bursting activity of the VTA can exert a frequency-dependent gating action over PFC neuron firing driven by inputs from the hippocampus. In light of these data, we were interested in assessing what role the VTA may play in modulating the interactions between MD and hippocampal inputs to the PFC. In nine PFC←Hipp neurons (nine rats) that also displayed a monosynaptic action potential in response to MD stimulation, we assessed how burst stimulation of the VTA modulated MD gating exerted over hippocampal-evoked firing, using our sequential-pulse stimulation protocol. For these experiments, we only used interpulse intervals of 10–50 msec, because we did not observe any significant effect of MD conditioning pulses applied >100 msec before FF test pulses, and the magnitude of inhibition of firing by MD conditioning pulses was equivalent at intervals of 25–100 msec.
Analysis of these data revealed a significant MD pulse × VTA stimulation interaction (F(2,16) = 5.8; p < 0.05) (Fig.9A). In these cells, the baseline firing probability evoked by MD stimulation and FF stimulation did not differ (FF mean = 59.5 ± 4%; MD mean = 63.9 ± 6%; F(1,8) = 0.7; NS). As observed previously (Fig. 2), delivery of a conditioning pulse to the MD 10 or 50 msec before stimulation of the FF significantly inhibited FF-evoked firing, when compared with firing evoked by single-pulse stimulation of the FF alone. The inhibition of FF-evoked firing by a conditioning pulse to the MD was significantly greater (p < 0.05) when the interval between pulses was 50 versus 10 msec (Fig. 9A). Burst stimulation of the VTA 10 msec before single-pulse stimulation of the FF also inhibited FF-evoked spike firing (p < 0.05). However, application of a conditioning pulse to the MD 10 msec after VTA stimulation, and 10 msec before FF stimulation (i.e., a VTA burst–MD pulse–FF pulse sequence), attenuated the VTA-mediated inhibition of FF-evoked firing. The hippocampal-evoked firing probability was significantly higher (p < 0.05) when compared with firing probability observed after VTA burst–FF stimulation alone. Moreover, at the 10 msec interval between MD and FF stimulation, there was no difference in the firing probabilities observed after a VTA–MD–FF sequence when compared with an MD–FF paired-pulse sequence. This effect was not observed when a longer, 50 msec interval between the MD conditioning pulse and FF test pulse was used. In this instance, a conditioning pulse to the MD 10 msec after VTA stimulation and 50 msec before FF stimulation caused no significant change in the FF-evoked firing probability, when compared with the reduced firing probability displayed after VTA stimulation alone. Thus, as observed previously, activation of either VTA or MD inputs to the PFC can inhibit evoked firing in PFC←Hipp neurons. However, during periods of VTA bursting activity, activation of PFC neurons by the MD that occurs nearly simultaneously with activation by hippocampal inputs converging on the same neuron can reduce the inhibitory actions that the VTA exerts over spike firing driven by the hippocampus.
Using different stimulation protocols, we report four primary observations: (1) in the majority of PFC←Hipp neurons tested, inputs from the MD exert a powerful inhibitory gating action over hippocampal-evoked firing; (2) repetitive burst stimulation of the MD potentiates hippocampal-evoked activity that lasts several minutes; (3) stimulation of the VTA inhibits hippocampal-evoked firing with a preferential attenuation of low-frequency inputs, an effect that was altered after selective blockade of DA receptors. D1 receptors facilitate higher-frequency transmission in the hippocampal-PFC pathway, whereas D2 and D4 receptors inhibit firing, and (4) the relative timing of inputs from the MD or VTA determines their impact on PFC neuron responses to hippocampal inputs. Activation of the MD ∼10 msec before activation of hippocampal inputs was less likely to inhibit hippocampal-evoked firing than at longer intervals. This last finding suggests that inputs from the MD may play a role in heterosynaptic coincidence detection (Usrey, 2002), inhibiting inputs from the temporal lobe unless they arrive synchronously with diencephalic inputs.
Modulation of the hippocampal–PFC pathway by the MD
Thalamocortical inputs from the MD typically exerted a pronounced inhibition of hippocampal-evoked firing in PFC neurons. Although there is only preliminary ultrastructural evidence that inputs from the MD synapse on PFC GABAergic interneurons (Kuroda et al., 1998), such an arrangement is commonly reported in other thalamocortical projection systems (Freund et al., 1985; Staiger et al., 1996), and activation of thalamocortical axons yields a threefold larger amplitude EPSP on fast-spiking interneurons as compared with pyramidal neurons (Beierlein and Connors, 2002). Furthermore, stimulation of the MD produces an EPSP–IPSP sequence in PFC neurons (Gigg et al., 1994; Lewis and O'Donnell, 2000), and chemical stimulation of the MD activatesc-fos immunoreactivity in PFC GABA-containing neurons (Bubser et al., 1998). In the present study, the inhibition of hippocampal-evoked firing after activation of glutamatergic MD afferents is likely mediated by feedforward inhibitory circuits. The fact that this effect was observed in the majority of PFC←Hipp neurons suggests that a large proportion of information that arrives from the hippocampus is under the modulatory control of the MD.
For PFC←Hipp neurons that did not fire in response to MD stimulation, activation of thalamocortical afferents with a train of stimuli (but not single pulses) attenuated hippocampal-evoked firing in a majority of neurons. This finding suggests that although relatively few PFC←Hipp neurons appeared to receive direct monosynaptic input from the MD, a larger proportion of these cells can still be modulated by MD inputs in a frequency-dependent manner. Reyes et al. (1998) reported that activity of neocortical GABAergic interneurons was facilitated when excitatory inputs were stimulated with a 10 Hz train. Thus, an increase in activity of MD inputs to the PFC in the 10–40 Hz range can filter a large ensemble of PFC←Hipp neurons, attenuating firing driven by temporal lobe inputs. This finding parallels phenomena observed in other thalamocortical systems, whereby thalamic nuclei can gate the flow of sensory inputs to the neocortex, producing widespread suppression of activity, thereby focusing cortical sensory representations (Castro-Alamancos, 2002; Castro-Alamancos and Oldford, 2002).
In contrast to the above-mentioned effects, 33% of the PFC←Hipp neurons displayed a facilitation of hippocampal-evoked firing after train stimulation of the MD, although MD stimulation alone did not evoke firing. Moreover, repeated trains of thalamic stimulation facilitated hippocampal-evoked firing for minutes after tetanus. These data, combined with those described above, suggests the presence of two distinct populations of PFC←Hipp neurons: one receives a predominantly inhibitory (presumably polysynaptic) input from the MD, and a second receives a weak excitatory input that by itself is insufficient to evoke spike firing. With respect to this latter population, intracellular recordings have shown that train stimulation of thalamic nuclei can produce an "augmenting response" in sensorimotor cortex, causing a sustained depolarization lasting hundreds of milliseconds (Castro-Alamancos and Connors, 1996; Steriade et al., 1998). This phenomenon is thought to originate in deep cortical layers and activates reverberatory circuits via intralaminar and horizontal collaterals. A similar mechanism may explain the effects observed here: high-frequency activation of subthreshold inputs to the MD would have depolarized a subpopulation proportion of PFC neurons (distinct from those that are inhibited by MD activation) and made them more responsive to hippocampal input.
VTA modulation of hippocampal-evoked firing of PFC neurons
Burst stimulation of the VTA induced a frequency-dependent inhibition over evoked firing in PFC←Hipp neurons; these effects were altered by systemic administration of DA antagonists. This observation complements previous findings in which activation of DA receptors promotes a frequency-dependent inhibition over synaptically evoked activity of PFC neurons (Jay et al., 1995; Gurden et al., 1999; Seamans et al., 2001). The faster-onset (>100 msec) D4-mediated inhibition and a longer-lasting D2-mediated attenuation of spike firing (∼300 msec) after a VTA burst may be related to the location of these receptors in the PFC. In addition to being localized on some pyramidal neurons, D2-like receptors in the PFC also reside on GABAergic interneurons (Mrzijak et al., 1996; Wedzony et al., 2001) and on excitatory presynaptic terminals (Sesack et al., 1995). Thus, multiple cellular mechanisms exist by which D2and D4 receptors could decrease the responsivity of PFC neurons to hippocampal inputs, including facilitation of GABA release (Retaux et al., 1991; Grobin and Deutch, 1998; Zhou and Hablitz, 1999), modulation of the resting membrane potential (Gulledge and Jaffe, 1998, Yang et al., 1999), and presynaptic inhibition of hippocampal inputs. Indeed, in the nucleus accumbens, application of D2 agonists altered hippocampal terminal excitability, implying that DA inhibits hippocampal inputs presynaptically (Yang and Mogenson, 1986). We observed a dramatic alteration in the paired-pulse ratio of FF-evoked firing after VTA stimulation (Fig. 6A), suggesting that mesocortical DA can also inhibit hippocampal inputs presynaptically.
Blockade of D1 receptors augmented the VTA-mediated inhibition of hippocampal-evoked firing, abolishing the frequency-dependent inhibition that was observed under control conditions. This finding implies that D1 receptor activity can offset the inhibitory actions of D2-like receptors on PFC neuron firing, thereby augmenting the probability that higher-frequency inputs will evoke spiking. These effects parallel those observed in vitroduring which excitatory inputs to PFC neurons were stimulated using 20 Hz trains (Seamans et al., 2001). Bath application of a D1 receptor agonist reduced the EPSP evoked in early parts of the train but enhanced the EPSP in latter parts of the train. In that study, it was found that the facilitatory effects of D1 receptors were co-mediated by NMDA receptors. We did not observe a role for NMDA receptor in the D1 modulation of evoked firing, suggesting that D1–NMDA interactions may play a more important role in modulating subthreshold EPSPs (Seamans et al., 2001; Wang and O'Donnell, 2001). Alternatively, D1 receptors could increase the excitability of PFC neurons by facilitating persistent Na+ (Yang and Seamans, 1996;Gorelova and Yang, 2000; Lavin and Grace, 2001) or Ca2+ conductances (Hernández-López et al., 1997; Wang and O'Donnell, 2001), which would enhance neuron excitability, facilitate temporal summation of inputs, and increase the probability that subsequent EPSPs evoked by latter parts of a train will evoke spiking.
A similar mechanism may underlie the interactions among MD, hippocampal, and VTA inputs to PFC neurons. VTA activation normally inhibits firing evoked by single pulses to the FF. However, impulses from the MD arriving nearly simultaneously with those from the hippocampus may depolarize the neuron, activating intrinsic currents that are susceptible to D1 receptor modulation (Lavin and Grace, 2001), which in turn would make the cell more responsive to hippocampal inputs. Collectively, these data suggest that during periods of increased VTA neuron bursting, impulse activity from the hippocampus that arrives either at a higher frequency or in close temporal proximity to impulses from the MD can be augmented by D1 receptor activity and are less likely to be inhibited by D2–like receptors. As such, inputs from the VTA may be viewed as a "high-pass filter," permitting higher-frequency inputs that exert a stronger depolarizing action and greater control over spike firing of PFC neurons.
Functional implications
Mnemonic processes mediated by the hippocampal–PFC circuits, such as working memory, are dependent on functional interactions between MD and mesocortical DA input (Gabriel, 1993; Freeman et al., 1996;Floresco et al., 1997, 1999). Similarly, inputs from both the MD and the mesocortical DA system have been implicated in other executive functions mediated by the PFC, such as behavioral flexibility (Hunt and Aggleton, 1998; Ragozzino et al., 1999; Ragozzino, 2002). The present data provide important insights regarding the cellular mechanisms that underlie cognitive processes subserved by neural networks incorporating the frontal and temporal lobes and thalamic and midbrain nuclei. For example, during periods in which reward is anticipated, increased bursting of VTA DA neurons (Schultz, 1998) should limit the flow of information from the hippocampus to the PFC, permitting only the most salient information, arriving in the form of higher-frequency trains of impulses, to evoke firing. Blockade of D1receptors in the PFC would be expected to attenuate mnemonic-related activity in PFC←Hipp neurons and impair working memory (Seamans et al., 1998). In addition, MD neurons also show increased delay-period activity during a delayed response task (Oyoshi et al., 1996). Our data suggest that a prolonged increase in MD activity may facilitate working memory processes, augmenting the excitability of PFC neurons and making them more responsive to information arriving from the hippocampus after a delay. On the other hand, the ability of both the MD and VTA DA inputs to facilitate or inhibit the activity of PFC←Hipp neurons may be viewed as a cellular component that permits strategy switching, facilitating the learning of a new behavioral strategy while at the same time inhibiting a previously learned response. Collectively, these data suggest that inputs from the MD and VTA that modulate the activity of PFC←Hipp neurons are essential components of cortical–subcortical networks that regulate information processing by the frontal lobes. Disruption in these components would be expected to result in disorganized information processing, behavioral inflexibility, and deficits in working memory. Interestingly, each of these symptoms are observed in schizophrenia, the pathophysiology of which is characterized by dysfunction in both the MD and hippocampal–PFC circuits, as well as a decrease in PFC D1receptor activity (Weinberger et al., 1994; Okubo et al., 1997; Akil et al., 1999; Friedman et al., 1999; Shenton et al., 2001). The present data suggest that decreased D1 receptor activity combined with a hyperexcitable mesolimbic DA system would reduce the transfer of information between the temporal and frontal lobes. Our finding that antipsychotic agents, acting on D2-like receptors, can alleviate the VTA-mediated inhibition of PFC←Hipp neurons suggests that their efficacy in treating psychosis may be attributable in part to their ability to normalize neural activity in these circuits that has been perturbed by alterations in D1 receptor activity.
This work was supported by United States Public Health Service Grants MH 01055, MF 57440, and MH 45156. S.B.F. is a recipient of a Human Frontiers Science Organization Post-Doctoral Fellowship. We thank Christy Smolak and Nicole MacMurdo for their assistance with histology and Pfizer for their generous donation of CP293,019.
Correspondence should be addressed to Dr. Stan B. Floresco, Department of Neuroscience, University of Pittsburgh, 446 Crawford Hall, Pittsburgh, PA, 15260. E-mail:floresco{at}brain.bns.pitt.edu.


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The Kālacakra world model is not mechanical
The following is a paper prepared for presentation at the Central Institute of Higher Tibetan Studies in Sarnath, India. To view or download a pdf version of this, please click here.
The short version of this paper would read: the Kālacakra system possesses a model of the world system, but it is qualitative, and not a mechanical model that could be used to derive calculations of solar, lunar and planetary positions. The Kālacakra system in fact lacks such a model, and the calculations used stem from older models that are not now preserved in the Kālacakra literature.
I should describe here first just what I mean by a mechanical model in this context. In modern physics, the model could be called dynamic. The Sun, Moon, Earth and other planets are described in terms of their sizes, masses, positions and velocities at any moment in time. The gravitational forces between them are described in terms of mathematical formulae, and from all these, their accelerations (changes in velocity) can be calculated and therefore their later positions.
This has now been achieved to a very high degree of accuracy, and systems are in place for calculating planetary positions several thousand years, both in the distant past and in the future. These modern systems are very complex, and as one who has computerised the most up-to-date formulae for deriving planetary positions, I can testify to their complexity – the longitude of the Sun alone contains over a thousand trigonometric expressions. It is these calculations that I have used in my interpretation of the Kālacakra calendar on this website.
Basically, given any one planet, from the dynamic information of its position, mass, velocity and the gravitational forces acting on it, we can calculate its future position.
It has been recognised by many writers that many of the early astronomical systems in India are derived from Greece, specifically the pre-Ptolemaic system of simple epicycles. These early Greek systems conceived of physical invisible spheres or circles that determined the positions of the planets. In these systems, the planets were considered to move in circles around points that themselves moved in circles around the Earth. The relative radii of these circle made a reasonably good model for the motion of the planets, and based on these, mathematics could be constructed that enabled the calculation of the real, as opposed to mean, motions of the planets. To a first degree of approximation, this can work pretty well.
The accuracy that the Greeks achieved was due to a combination of two things. They combined their geometric models of the solar system with the Babylonian sexagesimal (base 60) number system sometime in the 2nd century B.C.E. On this, Glen Van Brummelen writes: "The capacity afforded by efficient numeration transformed their astronomy, from the essentially qualitative model-building science of Eudoxus and Autolycus to the more familiar quantitative one of Hipparchus and Ptolemy. The explanatory models now became capable of predicting positions, not merely mimicking behaviour."
Many consider that this was the birth of true science. A model representing an aspect of the universe was constructed from which predictions could be made of planetary positions. The model was then adjusted in the light of observation, and quite reasonable accuracy achieved.
These pre-Ptolemaic calculations are the eccentric and epicycle-on-deferent techniques of Hipparchus and Apollonios. For what we would nowadays call the heliocentric component of a planet's motion, the planet is conceived as rotating in a circle, the centre of which is offset from the Sun. This is also exactly equivalent to having a point move around a circle centred on the Sun, and the planet move around this point in a smaller circle. If the centre of this smaller circle rotates once around the Sun every time the planet itself rotates around that point, then the planet describes a circle that is offset from the Sun. (See the diagram and explanation below.)
The deferent refers to the simple circle or sphere that is centred on the Sun or Earth and the epicycle is the smaller circle around which the planet moves. With the period of revolution of the deferent being equal to that of the period of the planet, and the epicycle having a period equal to that of the Earth, this model creates the important variation in the apparent speed of the planet, including the retrograde motion when the planet appears to move backwards against the stars.
The combination of these two – eccentric and epicycle-on-deferent – gives a good first approximation to the motions of the Sun, Moon and planets. Ptolemy later enhanced these concepts and created a much more elaborate system with many further cycles within cycles, but it is clear that the Kālacakra system uses mathematics that matches closely these pre-Ptolemaic systems – this shall be demonstrated later in this paper – but the Kālacakra contains no reference whatsoever to any such underlying model.
There is a model of the world system given in the Kālacakra, but it bears no relationship to the calculations; it cannot be used as the basis for any calculation. Interestingly, this model combines elements that are to be found in both Hindu and Jain systems as well as Buddhist. At the bottom are the disks of the four elements, with earth sitting at the top, and water, fire and wind beneath, each one having a larger diameter than the one above it. In the middle of the 100,000 yojana-diameter disk of earth sits a colossal five-peaked Mt. Meru, circular in cross-section, and 100,000 yojanas in height; it is wider at the top (50,000) than at the bottom (16,000).
Meru is surrounded by six alternating sets of continents, oceans, and mountain ranges. First is the circular continent of Candra, then the sweet ocean surrounded by the circular Nīlābha mountains. These are surrounded then by the continent of Sitabha, and so on. The diameter of the outermost Sīta mountains is 50,000 yojanas. This leaves a ring of ground, 25,000 yojanas wide, on which sit the 12 main continents, including our Jambudvīpa, sitting in oceans covering the rest of the upper surface of the disk of the earth. These comprise the seventh major continent. The rivers on these 12 continents flow into these oceans, which in turn flow into the great salty ocean that rises up from the protruding lower disk of the water element; this is the seventh great ocean. Finally, fire rising up from the disk of fire to a level somewhat above the level of the upper surface of the disk of earth forms the seventh great mountain range.
I have described this at some length in order to put the following in context: at a level approximately two thirds of the way up Mt. Meru circle the Sun and Moon, in circular orbits that are offset from the centre, that themselves also slowly rotate around Meru. This motion of the Sun around Meru in one day models two natural phenomena; the first being the daily change between day and night. However, in order to make this even close to reasonable, the idea has been introduced that the light from the Sun can only travel a certain distance – otherwise darkness would only exist in the shadow of Meru.
I hope the computer generated image of this above makes the point clear. In this first image the Sun is over the ocean beyond the semi-circular eastern continent of Videha. From the point of view of each continent, Meru is to the north, and so the Sun is well to the south of Videha – it is winter in Videha, and approximately midday. (Notice the Moon behind the Sun in this image.) In the western continent of Godānīya – barely visible on the left – it is midnight during the summer. (Click on this link for an animation illlustrating this.)
The second image below shows the orbit of the Sun in two different positions as seen from above. Towards the bottom of the image is our triangular continent of Jambudvīpa. The blue orbit gives winter in Jambudvīpa – when the Sun is at the lowest point in that orbit from the point of view of this image, it is over the ocean, far to the south of Jambudvīpa. When it is in an equivalent position in the red orbit, six months later, the Sun passes overhead of Jambudvīpa, and it is summer.
In this way, the orbit is considered to rotate around Mt. Meru, producing the changes of the seasons, and the Sun (together with the Moon) travels around the orbit bringing day and night to the continents. The planets, stars and lunar mansions (rgyu skar, nakṣatra) are not described clearly, but are considered to revolve above and behind the orbit of the Sun.
In addition to the problem I described regarding the need to have the Sun's rays only reach a certain distance, there are three other immediate problems with this model. For a start, such a Mt. Meru would be clearly visible in the sky. The Sun and Moon simply go out of sight because of their movement beyond the distance their light can reach, and they do not actually rise and set. Finally, at the moment of full Moon, the Sun and Moon are on opposite sides of Mt. Meru, and so the Moon would be in the shadow of Meru – and as a consequence, invisible. The Moon is hardly invisible at the time of full Moon!
It is easier to see these problems nowadays with modern computer simulations, but this is not a difficult scene to visualise, and there is no reason to assume that the Indian Kalacakra experts took it literally. It seems more likely that embodying the symbolism and the concepts associated with Meru and the continents and fitting in with these long existing traditions was of the greatest importance. This is clearly not a mechanical model. So, the only cosmological model that we have in the Kālacakra system is qualitative, and not suitable as a basis for calculations.
There have been many interactions between different societies, but one relevant thread is clear. The Babylonians with their advanced calculation system (derived from the Assyrians) became quite adept at predicting the motion of the planets, based simply on repeated observations over long periods of time. The Greeks took this further by combining these methods of calculation with their concept of models describing the motion of the planets, and basing their mathematics on the geometry of those models.
These calculation methods found their way to India, but the notion of the underlying models was not accepted or not considered necessary and did not take hold in Indian systems. Indian astronomers had to fit their inherited calculation systems with the observed motion of the Sun, Moon and planets, and the Hindu astronomers ended up by creating increasingly complex calculation systems as a result. The Buddhist Kālacakra system rejected this approach, accepts the small error in the motion of the Sun, and insists on adjusting the solar longitude simply in the light of observation. It was not considered necessary to construct complex calculations; just make regular adjustments. The relative motion of the Moon was very accurate in the system, and no doubt the planetary calculations seemed similarly satisfactory. It was the Sun that really mattered.
The calculations for the five planets as given in the Kālacakra literature can be shown to be derived from the Saura Siddhānta. If one takes the data given for this siddhānta by Varāhamihira (in his Pañcasiddhāntikā) for his epoch of 21st March 505 C.E., and calculates forward to the base Kālacakra epoch of 23rd March 806 C.E., you get the same data as given in the Tantra, including the replication of an error in Varāhamihira's data for Venus.
It was mentioned earlier that the Kālacakra system uses mathematics that matches closely pre-Ptolemaic systems. In the illustration above, the eccentric motion of a planet or the Sun is depicted. In the diagram below, on the left, the Earth (E) is offset from the centre (C) of the path of the planet (P). This is the eccentric model. The diagram on the right has the planet revolving in an epicycle around a point (C) that travels around the circular deferent. In this epicycle-on-deferent model, the period of rotation of the point C around the deferent is the same as the period of rotation of the planet about C. This means that the line CP is always pointing in the same direction – upwards in this diagram. This is exactly equivalent to the eccentric model, and the planet will travel in a circle that has its centre offset from the Earth by the same amount.
In the calculations, the first step is to convert from the mean position of the planet or Sun to the eccentric position – for the Sun this is the "true longitude" (nyi ma dag pa) and for a planet its "slow motion" (dal ba dag pa). We can see that the figures used in the Kālacakra literature are taken from an epicycle model by re-creating the basic calculations. All that is needed is to choose suitable radii for the deferent (EC) and epicycle (CP). We then use the cosine and sine rules to determine the angle PEC – this is the angle that has to be added to or subtracted from the mean motion to find the true slow motion. Using the cosine rule to find PE:
PE2 = EC2 + CP2 − 2.EC.CP.cos PCE
Having determined PE, we can then use the sine rule to find the angle PEC:
sin PEC / CP = sin PCE / PE
The results of these calculations are shown in the following tables for the five planets and then for the Sun. The first two figures are the values chosen for the radii of the deferent and the epicycle. The first column gives the value in degrees of the angle between the mean planet and the birth-sign. The difference between each is the size of one zodiac sign, 30°. The next column gives the calculated value of PE, and the next is the calculated value, in degrees, of PEC. In the next column, this is converted into the units used in the Kālacakra literature, nāḍī (chu tshod), correct to two decimal places. In the final column are the equivalent figures given in the Kālacakra literature.
In every single case, the calculated values agree closely with those in the Kālacakra system. We can do something similar for the Moon, this time taking steps of 13°.33, the length of a lunar mansion, given that there are 27 lunar mansion in a full circle:
The fit is not quite as good, but I do not know for certain that the originators of these numbers would have used exactly the methods that I am using. The Greeks, for example, used the chord function rather than sine and cosine. Also, the symmetry in the Kālacakra figures cannot be right – the same value 5 for the last row – half a mansion from a half-circle. This has to be wrong.
If instead we take 28 mansions in a full circle, we get:
Now the fit is better. This suggests that the Kālacakra figures were derived from a system that had 28, rather than 27, lunar mansions. Here is a perfect example of the kind of error that can occur if a mathematical system is separated from its model. We should perhaps expect to find a similar error in the figures for the fast motion of the planets.
Further on the point that the Greeks probably used slightly different calculations, we can take the example of Mars and, instead of calculating PE, use a simplified calculation of just one step, omitting the cosine rule for calculating PE, and using in the sine rule the value EC instead of PE. For a relatively small epicycle, such as with the Sun, this is a reasonable approximation, as EC and PE are of very similar lengths:
We now have a much better fit with the Kālacakra figures, and the numbers are symmetrical about the 90° point, just as are the Kālacakra values. If we do this for all the planets and the Sun, as given above, the results agree with the Kālacakra figures to the nearest whole number in every single case. This suggests that the Greeks, or whoever else calculated these tables, were indeed using more simplified versions of the calculations. These results are probably also closer to those that would be obtained using the old Greek chord tables. I have not yet been able to try repeating such calculations, and this would certainly be an interesting exercise.
From the point of view of the normal heliocentric system, E revolves around S, and P revolves more slowly (for the outer planets). From the point of view of a geocentric epicycle system, E remains stationary, S revolves around E in an orbit shown as a light line here, and the planet, P, revolves in the epicycle, around the point C. C is the centre of the epicycle, revolving around the deferent. The direction CP is equal to the direction ES, the longitude of the Sun from the Earth. The deferent and epicycle point of view is shown in the diagram on the right. For the inner planets this would represent the apparent motion of the Sun around the Earth as the deferent, and the epicycle as the motion of the planet around the Sun. The geometry is just the same as for the outer planets, but without the inner smaller circle for the orbit of the Sun. For the inner planets, we only consider the triangle PEC.
The geometry is very similar to that given above for the Sun, Moon and slow motions of the planets. The angle that needs to be determined in order to calculate the true position of the planet from the Earth, the direction indicated by EP, is the angle PEC. This is the difference between the mean and true positions of the planet. In the right-hand diagram, only these geocentric elements are shown.
By the cosine rule:
PE2 = CP2 + EC2 − 2.CP.EC.cos (180 − CPS)
Having found the length PE, by the sine rule:
sin PEC / CP = sin (180 − CPS) / PE
As before, the results are shown in the following tables.
The curious last couple of values for Mercury deserve further investigation – there is clearly something wrong. If we take steps assuming a complete circle of 28 rather than 27 lunar mansions, we get:
The fit is now much better, and the last couple of values do not have the large errors as in the previous table. It seems clear that for Mercury, at least, a 28 lunar mansion system was used. However, if we apply a similar calculation for the other planets using 28 mansions, the errors become greater. Mercury appears to be the odd one out here, and the figures for the other planets were calculated using a 27 lunar mansion system.
It is this type of work of the Greeks with epicycles that gave birth to the branch of mathematics that we know today as trigonometry. There is no doubt that the calculations that they used will be slightly different to the modern methods used here, and it is for this reason that we should expect small differences between the figures that I have derived and those presented in the Kālacakra literature.
However, the principle is clear enough; that the model that underpins the calculation systems given in the Kālacakra literature is an epicycle-on-deferent model, very similar to, if not exactly the same, as that developed by the Greeks, approximately 2,200 years ago. It should be clear that this epicycle-on-deferent model is very different from the Kālacakra cosmological model of Meru, the continents, and so forth. That clearly is of symbolic significance only, and should not in any sense be taken to represent a literal representation of the world system. The calculations that survive in the Kālacakra literature gave a reasonable approximation for the planetary, solar and lunar motions at the time that they were in use in India. But these calculations could not possibly be derived from the Meru-continents model, which we should consider to be qualitative.
However, mistakes have been made in this respect, most notably the view held by many Tibetans that the solstice is observed in Tibet two or three weeks (there is more than one system in use) before it is observed in India. This is quite simply wrong, and this view was based on a belief that the layout of the 12 continents and the motion of the Sun relative to them really did match the real world. This mistaken view led directly to the huge errors that we find in the solar longitude in modern Tibetan almanacs.
However, there is one reason why it is possible to have some sympathy with the Tibetans here. Although the methods described in the Kālacakra literature can only lead to a tropical zodiac, the difference between the tropical and sidereal zodiacs is not explicitly spelled out. The early Tibetan astronomers were clearly not aware of the distinction, and effectively assumed a sidereal zodiac.
Unfortunately, the amount of precession that had occurred during the previous several hundred years meant that the apparent position of the Sun in the lunar mansions of the fixed stars (sidereal zodiac) came in reasonable agreement with their expectations of the solar longitude, given the solstice's supposed early appearance. This clearly reinforced the view that the solstice time difference was real, as is made clear, for example, in the pad dkar zhal lung. As far as I am aware, it was only gzhon nu dpal who did not fall into this trap, because he strictly followed the Kālacakra solar longitude correction method at the time of winter solstice, and seems not to have taken the Meru-continents model as a literal representation of the world system.
It may not be possible to trace the exact origin of the values used in the Kālacakra calculations, but if further information does become available, it will be made available on this web site.
E. Henning. New Delhi, October, 2009.
Last updated 28 January 2013.
Return to Home Page.


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The death toll of Syrian refugees who froze to death due to a snowstorm in eastern Lebanon has risen to 15, according to Lebanese Civil Defense sources.
Six more bodies were found on Saturday, taking the death toll to 15, the sources said.
According to the sources, three children were among the victims, who lost their lives as they attempted to cross into Lebanon from neighboring Syria.
Three more refugees were rescued by Lebanese civil defense teams, the sources said.
On Friday, the Lebanese army said nine refugees had frozen to death along Lebanese-Syria border due to harsh weather.
The severe weather is expected to become sunny on Saturday and Sunday, according to Lebanese metrological agency.
Several parts of Lebanon -- including the Beqaa Valley, which is home to thousands of Syrian refugees -- have been hit recently with extremely cold weather and heavy snowfall.
Last month, the UN's refugee agency (UNHCR) said the number of registered Syrian refugees in Lebanon had fallen to about 998,000 from a previous 1.5 million.


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This is probably one of my favorite pieces. I just love the curved spindle like details on either side of the drawers. I am kicking myself now for not buying the rest of the set when I saw it.
It started out as an ordinary side table with the usual wear and tear...please ignore all the junk on top of it....
I decided to go wtih one of my new favorite color combos for this piece, gray and white. The white is crisp and clean and keeps it neutral and the gray just makes all those great details pop, especially the spindles.
I stuck with the original hardware on this because it just seemed to fit with it so nicely. It has a nice chunky feel. And I love the bun feet! They are one of my new favorite things for furniture. You will be seeing lots more of these from me... :)


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Yancey is a longtime Dallas resident, who is uniquely positioned to serve and fight for Texans. A veteran of the financial services industry, Yancey has helped build four successful investment management firms, which in turn, created hundreds of well-paying jobs. He is currently the Chairman and CEO of Attacca International, an independent, privately held mergers and acquisitions boutique firm based in Dallas. Yancey feels Texas is a model for economic and political success, and he would carry that model to Washington.
A Reagan Republican, Yancey is fiscally conservative, in favor of limited government, a strong military that embraces a "needs-based military spending metric," and supportive of strong free trade and economic development.
"Given the many challenges that America currently faces, this is the right time for a business leader to serve Texas and the country, rather than a career politician," Yancey says. "Senator Cornyn has little support from conservatives across Texas. Senator Cornyn has frequently disappointed Texans with his strong alignment with both Mitch McConnell and Trump. He has shown repeatedly that he is a follower and a compromiser on the wrong side of an issue rather than a leader. Conservative Texans deserve better! I ask for your support and your vote."
Yancey currently serves on the board of Emily's Place in Plano, Texas. Emily's Place is a home for women and their children to receive long-term, transformational care to break the cycle of domestic violence. He is also a board member of the Blue Sky Foundation, which uses the game of tennis (through the "Boots On The Court" program) to thank U.S. troops and their families for the sacrifices they make on a daily basis. Yancey is a prior co-owner of the WNBA Dallas Wings, having moved the team from Tulsa, Oklahoma to its current home in Arlington, Texas.
In addition to his private sector experience, Yancey is a member of Parkway Hills Baptist Church in Plano. Yancey earned his bachelor's degree from the University of Oklahoma and attended executive classes at Harvard University for advanced course studies in mergers and acquisitions. Yancey is married to Sherri Yancey and has two daughters, Alexann and Morgann Yancey.
For more information visit:


text:
Gesloten Cirkel – Submit X
FORMAT – 2xLP Album
LABEL – Murder Capital
GENRE – Techno,Electro,Acid
A1 – Zombiemaschine Acid
A2 – Zombiemaschine
A3 – Submit X
B1 – Stakapella
B2 – Stakan
B3 – Chatters
C1 – Ft Liette
C2 – Arrested Developemnt
D1 – Secret Area
D2 – Vader
Lots of techno artists go anonymous, but few do it with as much cheek as Gesloten Cirkel.
Submit X is a lot of things—fierce, catchy, brimming with personality. But most importantly, it's just an absurdly badass techno record.
Additional information
|0,8 kg


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Thursday, July 14, 2016
Summer Safety Tips for Dogs
24 comments :
GREAT advice...my peeps need to read this as I can be a little reckless at times, hehe!ReplyDelete
Loves and licky kisses
Princess Leah xxx
- AnonymousJuly 14, 2016 at 5:29 AM
All of these are valuable tips. I don't think I'll ever forget the one about the scissors. That picture is hilarious. Mom always worries about heat stroke when I take a street nap. She doesn't trust me to get up when I feel too hot. She gives me a minute of warmth and then starts rousting me up to get walking or go in the shade. Ugh.ReplyDelete
Love and licks,
You two are hilarious!!! I'm so happy we don't have poisonous snakes up here! If I ever came across one I might wet my fur!ReplyDelete
BOL! Toxic Waste and Scissors?!? Priceless....of course, great reminders for everyone about Summer Safety, boys.ReplyDelete
Excellent safety tips guys. Sam and I hope your summer stays safe and fun. ღReplyDelete
Excellent tips!!ReplyDelete
Thanks for the tips, boys! Love the scissors pic. The biggest issue for us is the heat and humidity. No long walks, even in the mornings and evenings, when temps are already use to 90; yikes!! Have a fun rest of the summer, guys!ReplyDelete
great info!!ReplyDelete
This is a great post - safety for our pets is so important.ReplyDelete
Mr Bailey, Hazel & Mabel
Pee es
Ally-gator is one of Mabel's favorites too - he goes in her crate with her when we are not at home. The first thing she does when we open the crate door is grab Ally-Gator to bring him with her. She will take him out with her to potty, tee hee
This is some very valuable information. Great post fellas!ReplyDelete
Your Pals,
Murphy & Stanley
Some great summer advice. Hope all pets are safe this summer.ReplyDelete
Great advice ! And many of them can apply to cats too. PurrsReplyDelete
Good safety tips, Bentley! I prefer to either be in the water, or in the a/c if it is hot out here. At sports events, I bring my fan along, and my ice collar to stay nicely chilled.ReplyDelete
Love the pictures!ReplyDelete
Great advice, boys! And some of these can apply to us cats, too.ReplyDelete
EXCELLENT EXCELLENT EXCELLENT POST!!!!!ReplyDelete
Excellent tips my friends. Everyone needs to read all these important factsReplyDelete
Lily & Edward
OMD, what a FABulous postie guys!!!! All great tips!!!! and I agree abouts the toxic waste...AVOID MA's COOKING AT ALL COSTS!!!! (I had to learn the hard way...don't ask...)ReplyDelete
Ruby ♥
Excellent tips!! It has been SO HOT here!! We are very glad to have A/C!ReplyDelete
Thanks so much for the wonderful reminders!ReplyDelete
Dory, Jakey, Arty & Bilbo
- AnonymousJuly 15, 2016 at 2:08 PM
I prefer "furry fmaily member" too.ReplyDelete
Great tips! We are glad we don't have to worry about snakes around here!ReplyDelete
Jan, Wag 'n Woof Pets
All excellent Summer safety tips, but I must agree with the boys toxic waste & scissors should top the list. LOL!!ReplyDelete
Love & biscuits,
Dogs Luv Us and We Luv Them
Wooftastic summer safety tips Bentley & Pierre!ReplyDelete
Scissors are definitely dangerous; my huMom is always saying how they need to be put away safely.
Snakes too can be quite dangerous but my pigbros GG & MiG have very little tolerance for snakes & will stomp them to death. GG will even stomp the garden hose if he sees it.
Thanks for another pawsome blog post my furiends.
Nose nudges,
CEO Olivia