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Thalamic paraventricular nucleus (PVT) neurons exhibit a postburst apamin-resistant slow afterhyperpolarization (sAHP) that is unique to midline thalamus, displays activity dependence, and is abolished in tetrodotoxin. Analysis of the underlying sI(AHP) confirmed a requirement for Ca(2+) influx with contributions from P/Q-, N-, L-, and R subtype channels, a reversal potential near E(K)(+) and a significant reduction by UCL-2077, barium or TEA, consistent with a role for K(Ca) channels. sI(AHP) was significantly reduced by activation of either the cAMP or the protein kinase C (PKC) signaling pathway. Further analysis of the sAHP revealed an activity-dependent but Ca(2+)-independent component that was reduced in high [K(+)](o) and blockable after Na(+) substitution with Li(+) or in the presence of quinidine, suggesting a role for K(Na) channels. The Ca(2+)-independent sAHP component was selectively reduced by activation of the PKC signaling pathway. The sAHP contributed to spike frequency adaptation, which was sensitive to activation of either cAMP or PKC signaling pathways and, near the peak of membrane hyperpolarization, was sufficient to cause de-inactivation of low threshold T-Type Ca(2+) channels, thus promoting burst firing. PVT neurons are densely innervated by orexin-immunoreactive fibers, and depolarized by exogenously applied orexins. We now report that orexin A significantly reduced both Ca(2+)-dependent and -independent sI(AHP), and spike frequency adaptation. Furthermore orexin A-induced sI(AHP) inhibition was mediated through activation of PKC but not PKA. Collectively, these observations suggest that K(Ca) and K(Na) channels have a role in a sAHP that contributes to spike frequency adaptation and neuronal excitability in PVT neurons and that the sAHP is a novel target for modulation by the arousal- and feeding-promoting orexin neuropeptides.

The thalamus has a key function in processing sensory information, sleep, and cognition. We examined the effects of a common volatile anesthetic, isoflurane, on modulation of neuronal excitability in reticular thalamic nucleus (nRT) in intact brain slices from immature rats. In current-clamp recordings, isoflurane (300-600 micromol/L) consistently depolarized membrane potential, decreased input resistance, and inhibited both rebound burst firing and tonic spike firing modes of nRT neurons. The isoflurane-induced depolarization persisted not only in the presence of tetrodotoxin, but after replacement of Ca(2+) with Ba(2+) ions in external solution; it was abolished by partial replacement of extracellular Na(+) ions with N-methyl-D-glucamine. In voltage-clamp recordings, we found that isoflurane slowed recovery from inactivation of T-type Ca(2+) current. Thus, at clinically relevant concentrations, isoflurane inhibits neuronal excitability of nRT neurons in developing brain via multiple ion channels. Inhibition of the neuronal excitability of thalamic cells may contribute to impairment of sensory information transfer in the thalamocortical network by general anesthetics. The findings may be important for understanding cellular mechanisms of anesthesia, such as loss of consciousness and potentially damaging consequences of general anesthetics on developing mammalian brains.

We examined the extent of the ferret prefrontal cortex (PFC) and its reciprocal connections with the mediodorsal nucleus of the thalamus (MD) by anterograde and retrograde labeling in 6- to 14-week-old male ferrets. Our results indicate that in the ferret, as in other species, MD projects heavily to the PFC although it also projects to other cortical and subcortical structures. The MD projection to PFC terminates largely in layer IV with lighter innervation of layers II, III, V, and VI. The cells projecting back to MD are mostly in layer VI. The parvocellular component of MD projects to and receives projections from the more caudal and dorsomedial component of the PFC, whereas the magnocellular portion of MD projects to and receives projections from the more rostral and lateral component of the PFC. With these results we have localized the ferret PFC, defined as a frontal cortical region with heavy reciprocal connections with the MD.

Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM) is a powerful surgical option in the treatment of tremor-predominant Parkinson's disease. However, its therapeutic efficacy depends on the tremor distribution. DBS is highly efficient in relief of distal appendicular tremor but not other types of tremor. Also, it is generally thought that DBS of the VIM has no significant beneficial effects on other motor symptoms of Parkinson's disease. We report two hemiparkinsonian patients, in whom unilateral VIM DBS combined with posteroventral pallidotomy produced long-lasting suppression of not only hand tremor, but also leg or jaw tremor and other motor symptoms.

In order to assess the role of continuous intracerebral infusion of GABA over the propagation of generalized seizures from the amygdala, Wistar rats were subjected to a kindling procedure at the left basolateral amygdala. Subsequently, they were implanted with miniosmotic pumps filled with 100mg/mL of GABA in saline, connected to catheters whose tips were placed bilaterally at both dorsomedian nuclei of the thalamus (DMNT). The threshold intensity to provoke local afterdischarges (ADT) and generalized seizures (GST) were measured before, during and after GABA infusion, as well as seizure intensity and signs of ataxia and sedation. While there was no observed variation on ADT, the median GST was significantly increased during, but not after infusion of GABA (P=0.047, compared to the preinfusion value). Seizure intensity was not changed. No signs of neurologic side effects were recorded. These data emphasize the role of DMNT in the generalization of seizures originated at the amygdala.

The involvement of thalamic midline nuclei (MLN) in early stage of Alzheimer's disease and in diencephalic amnesia has drawn attention to the connectivity between the nucleus reuniens (RE) and structures of medial temporal lobe. RE is major source of thalamic afferents to the hippocampus and has been shown to exert powerful excitatory action on CA1 of hippocampus, which is supposed to be involved in learning and memory processes. However, the role of the RE on spatial memory is a controversial issue. The present study was designed to evaluate the role of the RE in acquisition, consolidation and retrieval of spatial reference memory (RM) and working memory (WM). We assessed the effect of reversible inactivation of RE with tetracaine (0.5 microl, 2%) on different stages of memory. Rats were trained on RM and WM versions of the Morris water maze (MWM) task. RE was inactivated before or immediately after training or before the probe trial of retrieval tests. The data showed that reversible inactivation of the RE significantly impaired both RM and WM versions of MWM. Therefore, it seems that nucleus reuniens of thalamus plays a role in spatial RM and WM version of the MWM task in rats.

Rats with bilateral neurotoxic reuniens (RE), mediodorsal (MD), hippocampal (HIPP) or sham (SH) lesions were tested in a standard watermaze task, together with unoperated rats. RE-rats and SH-controls readily learned to swim directly to a hidden platform. In contrast, MD-rats displayed a transient deficit characterized initially by thigmotaxis. Like in previous studies, HIPP-rats had long latencies throughout training and displayed more random swims than the other groups. In a memory probe test with the platform removed, SH- and RE-rats approached the correct location relatively directly but, whereas SH-controls persistently searched in the training quadrant, RE-rats switched to searching all over the pool. The MD-group swam in loops to the platform, but then displayed persistent searching in the training quadrant. The HIPP-group performed at chance. These distinct patterns indicate that, although their search strategies were different, RE- and MD-rats had acquired sufficient knowledge about the platform location and could recall information in the probe test. All groups performed well in a subsequent cue test with a visible platform, with RE-rats initially escaping faster than the SH- and HIPP-groups, and MD-rats improving from an initially poorer level of performance to control level. This indicates that there were no sensorimotor or motivational deficits associated with any of the lesions. In conclusion, while the RE and MD nuclei seem not to be critical for the learning and memory of a standard watermaze task, they may contribute to non-mnemonic strategy shifting when animals are challenged in ways that do not occur during training.

Paraventricular thalamus (PvTh) is uniquely placed to contribute to reinstatement of drug and reward seeking. It projects extensively to regions implicated in reinstatement including accumbens shell (AcbSh), prefrontal cortex (PFC) and basolateral amygdala (BLA), and receives afferents from other regions important for reinstatement such as lateral hypothalamus. We used complementary neuroanatomical and functional approaches to study the role of PvTh in context-induced reinstatement (renewal) of extinguished reward-seeking. Rats were trained to respond for a reward in context A, extinguished in context B and tested in context A or B. We applied the neuronal tracer cholera toxin B subunit (CTb) to AcbSh and examined retrograde-labelled neurons, c-Fos immunoreactivity (IR) and dual c-Fos/CTb labelled neurons in PvTh and other AcbSh afferents. In PvTh there was c-Fos IR in CTb-positive neurons associated with renewal showing activation of a PvTh-AcbSh pathway during renewal. In PFC there was little c-Fos IR in CTb-positive or negative neurons associated with renewal. In BLA, two distinct patterns of activation and retrograde labelling were observed. In rostral BLA there was significant c-Fos IR in CTb-negative neurons associated with renewal. In caudal BLA there was significant c-Fos IR in CTb-positive neurons associated with being tested in either the extinction (ABB) or training (ABA) context. We then studied the functional role of PvTh in renewal. Excitotoxic lesions of PvTh prevented renewal. These lesions had no effect on the acquisition of reward seeking. These results show that PvTh mediates context-induced reinstatement and that this renewal is associated with recruitment of a PvTh-AcbSh pathway.

Cholinergic interneurons are the only known source of acetylcholine in the rat nucleus accumbens (nAcb); yet there is little anatomical data about their mode of innervation and the origin of their excitatory drive. We characterized the cholinergic and thalamic innervations of nAcb with choline acetyltransferase (ChAT) immunocytochemistry and anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) from the midline/intralaminar/paraventricular thalamic nuclei. The use of a monoclonal ChAT antiserum against whole rat ChAT protein allowed for an optimal visualization of the small dendritic branches and fine varicose axons of cholinergic interneurons. PHA-L-labeled thalamic afferents were heterogeneously distributed throughout the core and shell regions of nAcb, overlapping regionally with cholinergic somata and dendrites. At the ultrastructural level, several hundred single-section profiles of PHA-L and ChAT-labeled axon terminals were analyzed for morphology, synaptic frequency, and the nature of their synaptic targets. The cholinergic profiles were small and apposed to various neuronal elements, but rarely exhibited a synaptic membrane specialization (5% in single ultrathin sections). Stereological extrapolation indicated that less than 15% of these cholinergic varicosities were synaptic. The PHA-L-labeled profiles were comparatively large and often synaptic (37% in single ultrathin sections), making asymmetrical contacts primarily with dendritic spines (>90%). Stereological extrapolation indicated that all PHA-L-labeled terminals were synaptic. In double-labeled material, some PHA-L-labeled terminals were directly apposed to ChAT-labeled somata or dendrites, but synapses were never seen between the two types of elements. These observations demonstrate that the cholinergic innervation of rat nAcb is largely asynaptic. They confirm that the afferents from midline/intralaminar/paraventricular thalamic nuclei to rat nAcb synapse mostly on dendritic spines, presumably of medium spiny neurons, and suggest that the excitatory drive of nAcb cholinergic interneurons from thalamus is indirect, either via substance P release from recurrent collaterals of medium spiny neurons and/or by extrasynaptic diffusion of glutamate.

The thalamic paraventricular nucleus (PVT) receives afferents from numerous brain areas, including the hypothalamic suprachiasmatic nucleus (SCN), considered to be the major circadian pacemaker. The PVT also sends projections to the SCN, limbic system centers and some nuclei involved in the control of the Sleep-Wake cycle. In this study, we report the identification of a hitherto not reported direct retinal projection to the PVT of the rock cavy, a typical rodent species of the northeast region of Brazil. After unilateral intravitreal injections of cholera toxin subunit B (CTb), anterogradely transported CTb-immunoreactive fibers and presumptive terminals were seen in the PVT. Some possible functional correlates of the present data are briefly discussed, including the role of the PVT in the modulation of the circadian rhythms by considering the reciprocal connections between the PVT and the SCN. The present work is the first to show a direct retinal projection to the PVT of a rodent and may contribute to elucidate the anatomical substrate of the functionally demonstrated involvement of this midline thalamic nucleus in the modulation of the circadian timing system.

In all sensory systems, information is processed along several parallel streams. In the vibrissa-to-barrel cortex system, these include the lemniscal system and the lesser-known paralemniscal system. The posterior medial nucleus (POm) is the thalamic structure associated with the latter pathway. Previous studies suggested that POm response latencies are positively correlated with stimulation frequency and negatively correlated with response duration, providing a basis for a phase locked loop-temporal decoding of stimulus frequency. We tested this hypothesis by analyzing response latencies of POm neurons, in both awake and anesthetized rats, to vibrissae deflections at frequencies between 0.3 and 11 Hz. We found no significant, systematic correlation between stimulation frequency and the latency or duration of POm responses. We obtained similar findings from recording in awake rats, in rats under different anesthetics, and in anesthetized rats in which the reticular activating system was stimulated. These findings suggest that stimulus frequency is not reliably reflected in response latency of POm neurons. We also tested the hypothesis that POm neurons respond preferentially to sensor motion, that is, they respond to whisking in air, without contacts. We recorded from awake, head-restrained rats while monitoring vibrissae movements. All POm neurons responded to passive whisker deflections, but none responded to noncontact whisking. Thus like their counterparts in the trigeminal ganglion, POm neurons may not reliably encode whisking kinematics. These observations suggest that POm neurons might not faithfully encode vibrissae inputs to provide reliable information on vibrissae movements or contacts.

The auditory conditioned stimulus (CS) pathway that is necessary for delay eyeblink conditioning was investigated using reversible inactivation of the medial auditory thalamic nuclei (MATN) consisting of the medial division of the medial geniculate (MGm), suprageniculate (SG), and posterior intralaminar nucleus (PIN). Rats were given saline or muscimol infusions into the MATN contralateral to the trained eye before each of four conditioning sessions with an auditory CS. Rats were then given four additional sessions without infusions to assess savings from the initial training. All rats were then given a retention test with a muscimol infusion followed by a recovery session. Muscimol infusions through cannula placements within 0.5 mm of the MGm prevented acquisition of eyeblink conditioned responses (CRs) and also blocked CR retention. Cannula placements more than 0.5 mm from the MATN did not completely block CR acquisition and had a partial effect on CR retention. The primary and secondary effects of MATN inactivation were examined with 2-deoxy-glucose (2-DG) autoradiography. Differences in 2-DG uptake in the auditory thalamus were consistent with the cannula placements and behavioral results. Differences in 2-DG uptake were found between groups in the ipsilateral auditory cortex, basilar pontine nuclei, and inferior colliculus. Results from this experiment indicate that the MATN contralateral to the trained eye and its projection to the pontine nuclei are necessary for acquisition and retention of eyeblink CRs to an auditory CS.

The paraventricular (PV) and paratenial (PT) nuclei are prominent cell groups of the midline thalamus. To our knowledge, only a single early report has examined PV projections and no previous study has comprehensively analyzed PT projections. By using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin, and the retrograde tracer, FluoroGold, we examined the efferent projections of PV and PT. We showed that the output of PV is virtually directed to a discrete set of limbic forebrain structures, including 'limbic' regions of the cortex. These include the infralimbic, prelimbic, dorsal agranular insular, and entorhinal cortices, the ventral subiculum of the hippocampus, dorsal tenia tecta, claustrum, lateral septum, dorsal striatum, nucleus accumbens (core and shell), olfactory tubercle, bed nucleus of stria terminalis (BST), medial, central, cortical, and basal nuclei of amygdala, and the suprachiasmatic, arcuate, and dorsomedial nuclei of the hypothalamus. The posterior PV distributes more heavily than the anterior PV to the dorsal striatum and to the central and basal nuclei of amygdala. PT projections significantly overlap with those of PV, with some important differences. PT distributes less heavily than PV to BST and to the amygdala, but much more densely to the medial prefrontal and entorhinal cortices and to the ventral subiculum of hippocampus. As described herein, PV/PT receive a vast array of afferents from the brainstem, hypothalamus, and limbic forebrain, related to arousal and attentive states of the animal, and would appear to channel that information to structures of the limbic forebrain in the selection of appropriate responses to changing environmental conditions. Depending on the specific complement of emotionally associated information reaching PV/PT at any one time, PV/PT would appear positioned, by actions on the limbic forebrain, to direct behavior toward a particular outcome over a range of outcomes., ((c) 2008 Wiley-Liss, Inc.)

The firing behavior of 107 vestibular-sensitive neurons in the ventroposterior thalamus was studied in two alert squirrel monkeys during whole body rotation and translation in the horizontal plane. Vestibular-sensitive neurons were distributed primarily along the anterior and posterior borders of ventroposterior nuclei; three clusters of these neurons could be distinguished based on their location and inputs. Eighty-four neurons responded to rotation; 66 (78%) of them responded to rotation only and 18 (22%) to both rotation and translation. Forty-one neurons were sensitive to linear translation; 23 (56%) of them responded to translation only. The population rotational response to 0.5-Hz sinusoids with a peak velocity of 40 degrees /s showed a gain of 0.23 +/- 0.15 spike.s(-1).deg(-1).s(-1) and phase lagging behind the angular velocity by -9.3 +/- 34.1 degrees . Although rotational response amplitude increased with the stimulus velocity across the range 4-100 degrees /s, the rotational sensitivity decreased with and was inversely proportional to the stimulus velocity. The rotational response amplitude and sensitivity increased with the stimulus frequency across the range 0.2-4.0 Hz. The population response to sinusoidal translation at 0.5 Hz and 0.1 g amplitude had a gain of 111.3 +/- 53.7 spikes.s(-1).g(-1) and lagged behind stimulus acceleration by -71.9 +/- 42.6 degrees . Translational sensitivity decreased as acceleration increased and this was inversely proportional to the square root of the acceleration. Results of this study imply that changes in the discharge rate of vestibular-sensitive thalamic neurons can be approximated using power functions of the angular and linear velocity of spatial motion.

The posterior paraventricular nucleus of the thalamus (THPVP) has been identified as a forebrain region that modulates the central nervous system (CNS) response to recurrent experiences of stressors. The THPVP is activated in response to a single (SH) or recurrent (RH) experience of the metabolic stress of hypoglycemia. In this study, we evaluated whether temporary experimental inactivation of the THPVP would modify the neuroendocrine response to SH or RH. Infusion of lidocaine (LIDO) or vehicle had no effect on the neuroendocrine response to SH, comparable to findings with other stressors. THPVP vehicle infusion concomitant with RH resulted in a prevention of the expected impairment of neuroendocrine responses, relative to SH. LIDO infusion with RH resulted in significantly decreased glucagon and sympathoadrenal responses, relative to SH. These results suggest that the THPVP may contribute to the sympathoadrenal stimulation induced by hypoglycemia; and emphasizes that the THPVP is a forebrain region that may contribute to the coordinated CNS response to metabolic stressors.

The paraventricular nucleus of the thalamus (PVT) is part of a group of midline and intralaminar thalamic nuclei implicated in arousal and attention. This study examined the connections between the PVT and the forebrain by using the retrograde tracer cholera toxin B (CTb) and the anterograde tracer biotin dextran amine (BDA). The anterior and posterior regions of the PVT were found to send a dense projection to the nucleus accumbens. The posterior PVT was also found to provide a strong projection to the lateral bed nucleus of the stria terminalis (BST), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and central nucleus of the amygdala (CeA), regions associated with the extended amygdala. In contrast, the anterior PVT was found to send a weaker projection to the extended amygdala. The basolateral nucleus of the amygdala and the medial prefrontal cortex were found to receive a relatively weak projection from the PVT, and other regions of the BST and amygdala were found to be poorly innervated by the PVT. In addition, the PVT was found to innervate regions in the extended amygdala that contained corticotropin-releasing factor (CRF) neurons, many of which were found to receive apparent contacts from PVT fibers. The projection from the PVT to the nucleus accumbens and extended amygdala places the PVT in a key anatomical position to influence adaptive behaviors as well as the physiological and neuroendocrine responses associated with these behaviors., ((c) 2007 Wiley-Liss, Inc.)

Two thalamic nuclear groups, the anterior thalamic nuclei (ATN) and midline and intralaminar thalamic complex (MITC) have connections to the prefrontal cortex, amygdala, hippocampus and accumbens that are important for learning and memory. However, the anatomical proximity between the ATN and MITC makes it difficult to reveal their roles in memory retrieval of aversive conditioned behavior. To address the issue, we explored the activation of the ATN and MITC, as represented by the expression of the immediate early gene c-fos, following either the retrieval of a conditioned taste aversion (CTA) induced by taste-LiCl pairing (visceral aversion) or of inhibitory avoidance (IA) induced by context-foot shock pairing (somatic aversion) in rats. The anterodorsal (AD) nucleus in the ATN was activated by foot shock and the recall of IA, but not by i.p. injection of LiCl or the recall of CTA. No significant elevation was observed in the other ATN following these treatments. Among nuclei of the MITC, the paraventricular thalamic nucleus (PVT) was activated by the delivery of shock or LiCl and by the recall of both CTA and IA, while the mediodorsal thalamus (MD) and central medial and intermediate thalamus (CM/IMD) were not. The innately aversive taste of quinine did not elevate c-fos expression in either the ATN or MITC. These results suggest that the PVT in the MITC is involved in the processing and retrieval of both taste-malaise and context-shock association tasks, while the AD in the ATN is involved in those of context-shock association only. The difference of the activity between the ATN and MITC demonstrates their functional and anatomical heterogeneity in neural substrates for aversive learning tasks.

Rats can anticipate a fixed daily mealtime by entrainment of a circadian timekeeping mechanism anatomically separate from the light-entrainable circadian pacemaker located in the suprachiasmatic nucleus. Neural substrates of this food-entrainable circadian system have not yet been fully elucidated. A role for the thalamic paraventricular nucleus (PVT) is suggested by observations that scheduled feeding synchronizes daily rhythms of glucose utilization and immediate early gene and circadian clock gene expression in this area. One study has reported absence of food anticipatory circadian activity rhythms in rats with PVT ablations. To determine whether this effect extends to other behavioral measures of food anticipation, rats received large radiofrequency lesions aimed at the PVT and were maintained on a 3-h meal provided each day 6 h after lights-on. Rats with unambiguously complete PVT ablation exhibited increased total daily activity, a change in the waveform of the nocturnal activity rhythm, but no change in the amplitude, duration, latency to appearance or persistence during total food deprivation of food anticipatory activity measured by activity at or near a food bin accessible via a small window in the recording cage. These results indicate that, while the PVT may modulate light-entrainable rhythms, it is not a critical input, oscillator or output component of the circadian system by which rats behaviorally anticipate a daily mealtime.

The medial prefrontal cortex and the hippocampus serve well recognized roles in memory processing. The hippocampus projects densely to, and exerts strong excitatory actions on, the medial prefrontal cortex. Interestingly, the medial prefrontal cortex, in rats and other species, has no direct return projections to the hippocampus, and few projections to parahippocampal structures including the entorhinal cortex. It is well established that the nucleus reuniens of the midline thalamus is the major source of thalamic afferents to the hippocampus. Since the medial prefrontal cortex also distributes to nucleus reuniens, we examined medial prefrontal connections with populations of nucleus reuniens neurons projecting to hippocampus. We used a combined anterograde and retrograde tracing procedure at the light and electron microscopic levels. Specifically, we made Phaseolus vulgaris-leuccoagglutinin (PHA-L) injections into the medial prefrontal cortex and Fluorogold injections into the hippocampus (CA1/subiculum) and examined termination patterns of anterogradely PHA-L labeled fibers on retrogradely FG labeled cells of nucleus reuniens. At the light microscopic level, we showed that fibers from the medial prefrontal cortex form multiple putative synaptic contacts with dendrites of hippocampally projecting neurons throughout the extent of nucleus reuniens. At ultrastructural level, we showed that medial prefrontal cortical fibers form asymmetric contacts predominantly with dendritic shafts of hippocampally projecting reuniens cells. These findings indicate that nucleus reuniens represents a critical link between the medial prefrontal cortex and the hippocampus. We discuss the possibility that nucleus reuniens gates the flow of information between the medial prefrontal cortex and hippocampus dependent upon attentive/arousal states of the organism.

Background: Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. It is known that 17beta-estradiol induces apoptosis in anteroventral periventricular nucleus (AVPV) in rat brain. Also, there is evidence that consumption of soy isoflavones reduces the volume of AVPV in male rats. Therefore, in this study, we examined the influence of dietary soy isoflavones on apoptosis in AVPV of 150 day-old male rats fed either a soy isoflavone-free diet (Phyto-free) or a soy isoflavone-rich diet (Phyto-600)., Results: The occurrence of apoptosis in AVPV was examined by TUNEL staining. The incidence of apoptosis was about 10 times higher in the Phyto-600 group (33.1 +/- 1.7%) than in the Phyto-free group (3.6 +/- 1.0%). Furthermore, these apoptotic cells were identified as neurons by dual immunofluorescent staining of GFAP and NeuN as markers of astrocytes and neurons, respectively. Then the dopaminergic neurons in AVPV were detected by immunohistochemistry staining of tyrosine hydroxylase (TH). No significant difference in the number of TH neurons was observed between the diet treatment groups. When estrogen receptor (ER) alpha and beta were examined by immunohistochemistry, we observed a 22% reduction of ERbeta-positive cell numbers in AVPV with consumption of soy isoflavones, whereas no significant change in ERalpha-positive cell numbers was detected. Furthermore, almost all the apoptotic cells were ERbeta-immunoreactive (ir), but not ERalpha-ir. Last, subcutaneous injections of equol (a major isoflavone metabolite) that accounts for approximately 70-90% of the total circulating plasma isoflavone levels did not alter the volume of AVPV in adult male rats., Conclusion: In summary, these findings provide direct evidence that consumption of soy isoflavones, but not the exposure to equol, influences the loss of ERbeta-containing neurons in male AVPV.

Siberian hamsters exhibit several seasonal rhythms in physiology and behaviour, including reproduction, energy balance, body mass, and pelage colouration. Unambiguous long- and short day lengths stimulate and inhibit reproduction, respectively. Whether gonadal growth or regression occurs in an intermediate day length (e.g. 14 h L : 10 h D; 14L), depends on whether the antecedent day lengths were shorter (10L) or longer (16L). Variations in day length are encoded by the duration of nocturnal pineal melatonin secretion, which is decoded at several neural melatonin target tissues to control testicular structure and function. We assessed participation of three such structures in the acquisition and retrieval of day length information. Elimination of melatonin signalling to the nucleus reuniens (NRe), but not to the suprachiasmatic nucleus (SCN) or paraventricular thalamus (PVt), interfered with the acquisition of a long day reproductive response, whereas the obscuring of melatonin signals to the SCN and the NRe, but not to the PVt, interfered with the photoperiod history response. The SCN and NRe contribute in different ways to the melatonin-based system that mediates seasonal rhythms in male reproduction.

Summary The central nervous system (cerebral ganglion) of adult ascidians is linked to the neural gland complex (NGC), which consists of a dorsal tubercle, a ciliated duct and a neural gland. The function of the NGC has been the subject of much debate. The recent publication of the complete genomic sequence of Ciona intestinalis provides new opportunities to examine the presence and distribution of protein families in this basal chordate. We focus here on the ascidian neuropeptide G-protein-coupled receptors (GPCRs), the vertebrate homologues of which are involved in homeostasis. In situ hybridization revealed that five Ciona GPCRs [vasopressin receptor, somatostatin receptor, CRH (corticotropin-releasing hormone) receptor, angiotensin receptor and tachykinin receptor] are expressed in the NGC of adult ascidians. These findings, together with histological and ultrastructural data, provide evidence to support a role for the ascidian NGC in maintaining ionic homeostasis. We further speculate about the potential similarities between the ascidian NGC and the vertebrate choroid plexus, a neural peri-ventricular organ.

Neuropeptide S (NPS) is a newly identified transmitter that modulates arousal and anxiety. To determine potential neuronal targets for NPS, we studied the pattern of neuronal activation as indicated by the expression of Fos. Centrally administered NPS increased Fos-like immunoreactivity (FLI) in the paraventricular, dorsomedial nuclei and lateral hypothalamic area (LHA) of the hypothalamus, the midline thalamic nuclei, and the amygdala, many parts of which are involved in the regulation of emotion, arousal, and feeding. In particular, we noted that Fos-immunoreactive (Fos-ir) levels were increased in orexin-expressing neurons in the LHA. We then studied whether an icv injection of NPS increased food intake. The injection of NPS (1 nmol) significantly stimulated feeding at 2 h in rats, but there was no difference in food intake at 4 h or 24 h. These results suggest that arousal and feeding induced by NPS in the central nervous system may be related to the activation of orexin-expressing neurons.

The auditory conditioned stimulus (CS) pathway that is necessary for delay eyeblink conditioning was investigated with induced lesions of the medial auditory thalamus contralateral to the trained eye in rats. Rats were given unilateral lesions of the medial auditory thalamus or a control surgery followed by twenty 100-trial sessions of delay eyeblink conditioning with a tone CS and then five sessions of delay conditioning with a light CS. Rats that had complete lesions of the contralateral medial auditory thalamic nuclei, including the medial division of the medial geniculate, suprageniculate, and posterior intralaminar nucleus, showed a severe deficit in conditioning with the tone CS. Rats with complete lesions also showed no cross-modal facilitation (savings) when switched to the light CS. The medial auditory thalamic nuclei may modulate activity in a short-latency auditory CS pathway or serve as part of a longer latency auditory CS pathway that is necessary for eyeblink conditioning., (Copyright 2006 APA, all rights reserved.)

Unlike the basal ganglia input from the midline and intralaminar nuclei, the origin and prominence of striatal projections arising in the lateral thalamus varies considerably among mammals being most restricted in the opossum and monkey, most extensive in the rat. To get further insight into the evolution of thalamo-striatal pathways the Madagascar lesser hedgehog tenrec (Afrotheria) was investigated using anterograde and retrograde flow techniques. An extensive medial thalamic region (including presumed equivalents to the paraventricular, parataenial and dorsomedial nuclei as well as the reuniens complex), the rostral (central) and caudal (parafascicular) intralaminar nuclei were shown to give rise to striatal projections. Additional projections originated in the ventral anterolateral nuclear group and regions within and around the medial geniculate complex. Similar to the rat there was also substantial projections from the lateral posterior-pulvinar complex and the ventral posterior nucleus. The fibers terminated extensively across the striatum in a mainly homogeneous fashion. Isolated patches of low-density terminations were found in the caudoputamen. This inhomogeneous labeling pattern appeared similar to one described in the cat with the unlabeled islands showing features of striosomes. The medial and intralaminar nuclei also projected heavily upon the olfactory tubercle. Differential innervation patterns were noted in the polymorphous layer, the deep and the superficial molecular layer.

The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. The present report examined the effects of stimulation of the midline thalamus, concentrating on ventral nuclei of the midline thalamus, on evoked activity at the mPFC. The nucleus reuniens (RE) of the ventral midline thalamus is a major source of projections to the hippocampus and to the mPFC, and has been shown to exert pronounced excitatory effects on the hippocampus. No previous study has systematically examined the actions of the ventral midline thalamus on the mPFC. We showed that stimulation of the dorsal and ventral midline thalamus, but not of an intermediate region lying between them (null zone), produced short latency, large amplitude evoked potentials throughout the dorsoventral extent of the medial PFC. The largest effects were elicited with ventral midline stimulation (rhomboid/reuniens nuclei) at the ventral mPFC--the prelimbic (PL) and infralimbic (IL) cortices. Specifically, stimulation of RE produced evoked potentials (early negative component, N2) at the PL cortex at a mean latency of 22.6 msec and mean amplitude of 0.85 mV, indicative of monosynaptic effects. In addition, we showed that paired pulse stimulation of RH/RE produced strong facilitatory actions (paired pulse facilitation) at IL (83%) and PL (75%). These findings indicate that RE exerts strong direct excitatory effects on the mPFC, and coupled with the demonstration that RE produces similar actions on the hippocampus, indicates that RE is in a position to influence and possibly coordinate the activity of these two forebrain structures subserving memory., ((c) 2006 Wiley-Liss, Inc.)

The paraventricular thalamic nucleus (PVT) receives one of the most dense innervations by hypothalamic hypocretin/orexin (Hcrt) neurons, which play important roles in sleep-wakefulness, attention, and autonomic function. The PVT projects to several loci, including the medial prefrontal cortex (mPFC), a cortical region involved in associative function and attention. To study the effect of Hcrt on excitatory PVT neurons that project to the mPFC, we used a new line of transgenic mice expressing green fluorescent protein (GFP) under the control of the vesicular glutamate-transporter-2 promoter. These neurons were retrogradely labeled with cholera toxin subunit B that had been microinjected into the mPFC. Membrane characteristics and responses to hypocretin-1 and -2 (Hcrt-1 and -2) were studied using whole cell recording (n > 300). PVT neurons showed distinct membrane properties including inward rectification, H-type potassium currents, low threshold spikes, and spike frequency adaptation. Cortically projecting neurons were depolarized and excited by Hcrt-2. Hcrt-2 actions were stronger than those of Hcrt-1, and the action persisted in TTX and in low calcium/high magnesium artificial cerebrospinal fluid, consistent with direct actions mediated by Hcrt receptor-2. Two mechanisms of Hcrt excitation were found: an increase in input resistance caused by closure of potassium channels and activation of nonselective cation channels. The robust excitation evoked by Hcrt-2 on cortically projecting glutamate PVT neurons could generate substantial excitation in multiple layers of the mPFC, adding to the more selective direct excitatory actions of Hcrt in the mPFC and potentially increasing cortical arousal and attention to limbic or visceral states.

Periventricular hemorrhage (PVH) in the brain of premature infants is often associated with developmental delay and persistent motor deficits. Our goal is to develop a rodent model that mimics the behavioral phenotype. We hypothesized that autologous blood infusion into the periventricular germinal matrix region of neonatal rats would lead to immediate and long-term behavioral changes. Tail blood or saline was infused into the periventricular region of 1-day-old rats. Magnetic resonance (MR) imaging was used to demonstrate the hematoma. Rats with blood infusion, as well as saline and intact controls, underwent behavior tests until 10 weeks age. Blood-infused rats displayed significant delay in motor development (ambulation, righting response, and negative geotaxis) to 22 days of age. As young adults, they exhibited impaired ability to stay on a rotating rod and to reach for food pellets. MR imaging at 10 weeks demonstrated subsets of rats with normal appearing brains, focal cortical infarcts, or mild hydrocephalus. There was a good correlation between MR imaging and histological findings. Some rats exhibited periventricular heterotopia and/or subtle striatal abnormalities not apparent on MR images. We conclude that autologous blood infusion into the brain of neonatal rats successfully models some aspects of periventricular hemorrhage that occurs after premature birth in humans.

Sexual dimorphisms in the hypothalamus are mediated in several cases by local aromatization of androgens to estrogens during the perinatal period. In this series of experiments, the contributions of the two estrogen receptors (ERs), ERalpha and ERbeta, to the differentiation of the sexually dimorphic subpopulation of dopaminergic neurons in the anteroventral periventricular area (AVPV) was examined. In the first experiment, numbers of tyrosine hydroxylase (TH) immunoreactive (-ir) AVPV neurons in ERbeta knockout and wild-type (WT) mice of both sexes were measured. In the second experiment, the average number of TH-ir neurons in the medial portion of the AVPV in ERalpha knockout, ERbeta knockout, double-ER knockout, and WT mice of both sexes was calculated. In both experiments TH-ir cell numbers were sexually dimorphic as expected, with female individuals of all genotypes exhibiting more TH-ir neurons than WT males. Interestingly the average number of TH-ir neurons in all knockout males was significantly higher than in WT male littermates. In fact, TH-ir cell numbers in all knockout males were equivalent to females. In a final experiment, C57BL/6J female mice were treated during the first 3 postnatal days with either estradiol, or a specific agonist for one of the two ERs. Additional male and female pups received vehicle injections. Treatments with estradiol or either ER-specific agonist significantly reduced the number of TH-ir AVPV neurons in female brains. Our data demonstrate that both ERalpha and ERbeta are involved in the sexual differentiation of the AVPV in mice.

Food is considered a potent Zeitgeber for peripheral oscillators but not for the suprachiasmatic nucleus (SCN), which is entrained principally by the light-dark cycle. However, when food attains relevant properties in quantity and quality, it can be a potent Zeitgeber even for the SCN. Here we evaluated the entrainment influence of a daily palatable meal, without regular food deprivation, on the circadian rhythm of locomotor activity and the c-Fos and PER-1 protein expression in the SCN. Rats fed ad libitum, in constant darkness, received a palatable meal for 6 weeks starting in the middle of the subjective day. Locomotor activity showed entrainment when the offset of activity coincided with the palatable meal-time. In the SCN, the peak expression of c-Fos was observed at palatable meal-time and PER-1 showed a peak during the onset of subjective night, as predicted according to the behavioural entrained pattern. In addition, c-Fos and PER-1 expression in the paraventricular thalamic nucleus (PVT) showed increased expression at palatable meal-time, while the intergeniculate leaflet did not, suggesting that the PVT may be involved as an input pathway of palatable food-entrainment to the SCN. These results demonstrate that daily access to a palatable meal can entrain the SCN; several stimuli can be implicated in this process, including motivation and arousal.

Relaxin-3 (INSL-7) is a recently discovered member of the insulin superfamily. Relaxin-3 mRNA is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to the LGR7 receptor and to the previously orphan G protein-coupled receptor GPCR135. GPCR135 mRNA is expressed predominantly in the central nervous system, particularly in the paraventricular nucleus (PVN). The presence of relaxin-3 and these receptors in the PVN led us to investigate the effect of central administration of relaxin-3 on food intake in male Wistar rats. The receptor involved in mediating these effects was also investigated. Intracerebroventricular injections of human relaxin-3 (H3) to satiated rats significantly increased food intake 1 h post administration in the early light phase [0.96 +/- 0.16 g (vehicle) vs. 1.81 +/- 0.21 g (180 pmol H3), P < 0.05] and the early dark phase [2.95 +/- 0.45 g (vehicle) vs. 4.39 +/- 0.39 g (180 pmol H3), P < 0.05]. Intra-PVN H3 administration significantly increased 1-h food intake in satiated rats in the early light phase [0.34 +/- 0.16 g (vehicle) vs. 1.23 +/- 0.30 g (18 pmol H3), P < 0.05] and the early dark phase [4.43 +/- 0.32 g (vehicle) vs. 6.57 +/- 0.42 g (18 pmol H3), P < 0.05]. Feeding behavior increased after intra-PVN H3. Equimolar doses of human relaxin-2, which binds the LGR7 receptor but not GPCR135, did not increase feeding. Hypothalamic neuropeptide Y, proopiomelanocortin, or agouti-related peptide mRNA expression did not change after acute intracerebroventricular H3. These results suggest a novel role for relaxin-3 in appetite regulation.

1. Thermoregulatory effector mechanisms are strongly influenced by hydration status. Dehydration delays the onset of evaporative heat loss and the redistribution of cardiac output in response to elevations in core temperature, yet very little is known about how and where thermal and non-thermal information is integrated. 2. The anteroventral third ventricular (AV3V) region encompasses several distinct neural structures, including the organum vasculosum of the lamina terminalis, the median preoptic nucleus, the preoptic periventricular nucleus and the medial aspects of the medial preoptic nucleus. In addition to its well-documented role in body fluid and cardiovascular homeostasis, recent anatomical and in vitro evidence has indicated the AV3V region may also be pivotal in the integration of thermal and osmotic information. 3. Electrolytic lesions of the AV3V region produce a markedly reduced thermal tolerance in rats. Elevations in mean arterial pressure, heart rate and mesenteric resistance were all attenuated in the AV3V-lesioned animals in response to a heat stress; however, hindquarter resistance was unaffected. Heat-induced salivation was also attenuated, severely reducing the ability of rats to lose heat via evaporation. 4. The AV3V region clearly has a functional role in thermoregulation, as well as cardiovascular and body fluid homeostasis. These data add further support to the hypothesis that thermal and non-thermal information may be integrated within this region.

The nucleus reuniens (RE) is the largest of the midline nuclei of the thalamus and the major source of thalamic afferents to the hippocampus and parahippocampal structures. Nucleus reuniens has recently been shown to exert powerful excitatory actions on CA1 of the hippocampus. Few reports on any species have examined afferent projections to nucleus reuniens. By using the retrograde anatomical tracer Fluorogold, we examined patterns of afferent projections to RE in the rat. We showed that RE receives a diverse and widely distributed set of afferents projections. The main sources of input to nucleus reuniens were from the orbitomedial, insular, ectorhinal, perirhinal, and retrosplenial cortices; CA1/subiculum of hippocampus; claustrum, tania tecta, lateral septum, substantia innominata, and medial and lateral preoptic nuclei of the basal forebrain; medial nucleus of amygdala; paraventricular and lateral geniculate nuclei of the thalamus; zona incerta; anterior, ventromedial, lateral, posterior, supramammillary, and dorsal premammillary nuclei of the hypothalamus; and ventral tegmental area, periaqueductal gray, medial and posterior pretectal nuclei, superior colliculus, precommissural/commissural nuclei, nucleus of the posterior commissure, parabrachial nucleus, laterodorsal and pedunculopontine tegmental nuclei, nucleus incertus, and dorsal and median raphe nuclei of the brainstem. The present findings of widespread projections to RE, mainly from limbic/limbic-associated structures, suggest that nucleus reuniens represents a critical relay in the transfer of limbic information (emotional/cognitive) from RE to its major targets, namely, to the hippocampus and orbitomedial prefrontal cortex. RE appears to be a major link in the two-way exchange of information between the hippocampus and the medial prefrontal cortex., (2004 Wiley-Liss, Inc.)

To investigate which brain regions are involved in the anticipatory activity in rats restricted feeding for 2 hr, we examined c-Fos expression before and after feeding. Only the thalamic paraventricular nucleus (tPVN) showed c-Fos expression before feeding than after feeding. After the anticipatory locomotor activity rhythm was established, lesioning the tPVN attenuated this rhythm, but not the light-dark entrained rhythm. The anticipatory increase of blood corticosterone levels was not established in long-term tPVN-lesioned rats. These results suggest that the tPVN is involved in the expression of anticipatory reactions under a food-restricted regimen.

The vasoactive peptide urotensin-II and its receptor, GPR14 (now known as UT receptor), are localised in the mammalian central nervous system. Accordingly, various centrally mediated effects of urotensin-II on behaviour, neuroendocrine hormones and neurochemistry have been described. To investigate neuroanatomical substrates for the central actions of urotensin-II, expression of the immediate early gene c-fos was examined following intracerebroventricular administration to rats. Urotensin-II increased Fos expression in the cingulate cortex and periaqueductal grey, suggesting important central roles for urotensin-II and its receptor., (Copyright 2004 Elsevier B.V.)

Growth hormone (GH) pulsatility requires periventricular-nuclear somatostatin(SRIF(PeV)), arcuate-nuclear (ArC) GH-releasing hormone (GHRH), and systemic GH autofeedback. However, no current formalism interlinks these regulatory loci in a manner that generates self-renewable GH dynamics. The latter must include in the adult rat 1) infrequent volleys of high-amplitude GH peaks in the male, 2) frequent discrete low-amplitude GH pulses in the female, 3) disruption of the male pattern by severing SRIF(PeV) outflow to ArC, 4) stimulation of GHRH and GH secretion by central nervous system delivery of SRIF, 5) inhibition of GH release by central exposure to GHRH, and 6) a reboundlike burst of GHRH secretion induced by stopping peripheral infusion of SRIF. The present study validates by computer-assisted simulations a simplified ensemble formulation that predicts each of the foregoing six outcomes, wherein 1) blood-borne GH stimulates SRIF(PeV) secretion after a long time latency, 2) SRIF(PeV) inhibits both pituitary GH and ArC GHRH release, 3) ArC GHRH and SRIF(ArC) oscillate reciprocally with brief time delay, and 4) SRIF(PeV) represses and disinhibits the putative GHRH-SRIF(ArC) oscillator. According to the present analytic construction, time-delayed feedforward and feedback signaling among SRIF(PeV), ArC GHRH, and SRIF(ArC) could endow the complex physiological patterns of GH secretion in the male and female.

In the present studies, we examined the effects of chronic restraint on behavior in the conditioned defensive burying paradigm, a well-validated test of anxiety. This test is based on the findings that rodents tend to cover or bury the source of a noxious or aversive stimulus. However, little is known about whether prior chronic stress exposure can alter this anxiety-related behavior. In the present study, we examined whether chronic restraint affects indices of behavior in the conditioned defensive burying paradigm. Furthermore, since the posterior division of the paraventricular thalamus (pPVTh) regulates neuroendocrine activity specifically in chronically stressed but not control rats, we hypothesized that the pPVTh may also regulate any chronic stress-induced changes in behavior observed in the defensive burying test. Chronically stressed rats (30-min restraint per day for seven consecutive days) exhibited decreased latency to bury compared to control rats regardless of the presence of lesions suggesting increased reactivity to the shock in these animals. Importantly, pPVTh-lesioned chronically stressed rats exhibited increased duration and height of burying compared to control rats with pPVTh lesions, whereas no differences existed between sham-lesioned control and chronically stressed rats. Since both burying height and duration of burying are considered indices of anxiety in the defensive burying test, the present results suggest that the intact pPVTh may be important in dampening behaviors related to anxiety in chronically stressed rats.

The parvocellular subparafascicular thalamic nucleus (SPFp) is located in the posterior thalamus, consists of horizontally oriented cells, and extends from rostromedial to caudolateral, fusing with the posterior intralaminar nucleus and the peripeduncular nucleus. The present study demonstrates a chemoarchitechtonic and functional parcellation of the rat SPFp. Analysis of the distributions of the neuropeptides galanin, calcitonin gene related peptide (CGRP), substance P, and calbindin revealed the existence of a medial and lateral subdivision within SPFp, and a possible intermediate subdivision. The medial subdivision contains a dense population of galanin-immunoreactive fibers, originating from galanin neurons in the lumbosacral spinal cord. In contrast, the lateral subdivision contains CGRP-positive fibers and neurons. The presence of substance P and calbindin immunoreactivity throughout the entire nucleus suggests that these are separate subdivisions of SPFp, rather than different subnuclei. The present study also investigated the functional association of the separate subdivisions of SPFp for male and female rat sexual behavior. In the medial subdivision, Fos-positive neurons were activated in males by display of ejaculation and in females by vaginocervical stimulation. Thus, Fos induction in medial SPFp appears to reflect processing of inputs related to those events. In contrast, sexual behavior did not induce Fos in the lateral SPFp. Taken together, the present results indicate the existence of separate subdivisions in SPFp that are involved in different behavioral functions. The medial SPFp may process inputs important for sexual behavior, whereas the lateral SPFp may be involved in convergence of auditory and nociceptive inputs important for conditioned fear responses., (Copyright 2003 Wiley-Liss, Inc.)

Sexually dimorphic brain volumes (sexually dimorphic nucleus of the preoptic area (SDN-POA) and anteroventral periventricular (AVPV) nucleus) are influenced by estrogens. Phytoestrogens, derived from plants (especially soy products), are molecules structurally and functionally similar to estradiol. The purpose of this study was to examine: the consumption of phytoestrogen (using a phytoestrogen-rich (Phyto-600) versus a phytoestrogen-free (Phyto-free)) diets from conception to adulthood (or changing the diets during adulthood) and characterizing (a) circulating plasma phytoestrogen levels, (b) testosterone levels in males, (c) sexually dimorphic brain volumes (i.e. the SDN-POA and AVPV) and (d) the presence of apoptotic cells in these brain structures in Long-Evans rats. Phyto-600 fed animals displayed total serum phytoestrogens levels 37-fold higher compared to Phyto-free values. Circulating testosterone levels were not significantly altered by the diets. Female SDN-POA volumes were not altered by the diets. Whereas, males fed a Phyto-free diet displayed decreased SDN-POA volumes compared to male Phyto-600 values. Females fed the Phyto-600 diet displayed larger AVPV volumes compared to males on the same diet or females on the Phyto-free diet. Males fed the Phyto-free diet had the largest AVPV values compared to Phyto-600 fed males. When the SDN-POA region was examined in lifelong Phyto-free fed males, apoptotic cells were present versus males fed the Phyto-600 diet and in the AVPV region the opposite results were obtained. In summary, consumption of dietary phytoestrogens (estrogen mimics) can alter hormone-sensitive hypothalamic brain volumes in rodents during adulthood.

The paraventricular nucleus of the thalamus (PVT) participates in the functional integration of limbic cortical and striatal circuitry. In the rat, the PVT projects to the deep layers of the medial prefrontal cortex (PFC) and to the shell of the nucleus accumbens (NAc). However, the synaptic organization of PVT afferents within these regions remains undescribed. Furthermore, although dopamine (DA) modulates excitatory glutamate transmission in both areas, possible anatomic substrates for specific DA modulation of PVT inputs have not yet been investigated. To address these issues, immunoperoxidase labeling for tyrosine hydroxylase (TH) in DA axons was combined with anterograde tract-tracing, either by biotinylated dextran amine (BDA) labeled with immunogold-silver or by degeneration after lesions of the PVT. In both regions, and with either tracing method, PVT terminals formed primarily asymmetric axospinous synapses; in the NAc, a proportion of PVT terminals also synapsed onto dendrites. PVT profiles in both regions were often seen in direct apposition to TH-immunoreactive axons; this association was more evident in the NAc where the DA innervation is denser. Within the PFC, PVT profiles and TH-labeled axons were occasionally apposed to the same dendrites, but synaptic specializations were not typically seen at these seeming points of convergence. Within the NAc, PVT profiles occasionally made synapses onto spines and distal dendrites that received convergent synapses from TH-immunoreactive varicosities. These findings represent the first demonstration of postsynaptic convergence between DA and thalamic afferents to a striatal region and are consistent with direct synaptic modulation of PVT transmission by DA in the NAc but not the PFC., (Copyright 2003 Wiley-Liss, Inc.)

A gradual decrement in hypothalamic-pituitary-adrenal (HPA) activity is observed following repeated exposure to the same stressor, such as repeated restraint. This decrement, termed habituation, may be partly due to alterations in corticosterone-mediated negative feedback inhibition of the HPA axis. We have previously found that the posterior division of the paraventricular thalamus (pPVTh) regulates habituated HPA activity without altering HPA responses to acute stress. Therefore, in the present study, we examined the role of the pPVTh in delayed feedback inhibition of plasma corticosterone responses to repeated restraint. Dexamethasone was administered subcutaneously 2 h prior to 30 min restraint to induce delayed negative feedback inhibition of the HPA axis. In the first experiment, we determined that a 0.05-mg/kg dose of dexamethasone produced submaximal suppression of corticosterone responses to acute restraint and used this dose in the remainder of the experiments. In Experiment 2, we examined dexamethasone-induced feedback inhibition to corticosterone responses to a single or eighth restraint exposure since negative feedback functions in chronically stressed rats are not well studied. We found that corticosterone levels following dexamethasone treatment were similar in repeatedly restrained compared to acutely restrained rats. In Experiment 3, we lesioned the pPVTh and examined dexamethasone-induced feedback inhibition of corticosterone responses to a single or eighth exposure to restraint. pPVTh lesions attenuated dexamethasone-induced inhibition of corticosterone at 30 min in chronically stressed rats but had no effect in acutely stressed rats. These data suggest that negative feedback functions are maintained in rats exposed to repeated restraint and implicate the pPVTh as a site that contributes to these negative feedback functions specifically under chronic stress conditions.

Discharge properties in response to intracellularly applied, rectangular currents were measured in units of the mid (lateralis dorsalis and centrolateral nuclei) and posterolateral (lateralis posterior and pulvinar nuclei) thalamus of conscious cats. A separate aim was to determine if neuronal excitability changed in association with changes in stimulus-evoked activity after the animals were trained to discriminate between two acoustic stimuli when performing a conditioned motor response. Low threshold spike (l.t.s.) discharges were observed in three of 272 cells given 1 nA intracellular, hyperpolarizing current pulses of 40 ms duration. This finding supports the view that thalamic neurons of conscious animals operate mainly in the relay as opposed to the oscillatory mode. Application of larger and longer hyperpolarizing currents in the cells produced rebound l.t.s. discharges, supporting the expectation that most thalamic neurons are capable of producing this type of discharge. Decrements of spike afterhyperpolarizations (AHP) and broadening of spike bases upon repeated discharge also were observed in each area of the thalamus studied. After conditioning, changes were found in the posterolateral thalamus (but not in the mid-thalamus) in the proportions of cells with spontaneous, rapid (>/=50 Hz), repetitive, discharges (RRD) and rapid, sustained discharges at rates >/=100 Hz during application of depolarizing current (RSD). In the posterolateral thalamus the percentage of units responding to 1 nA depolarization with RSD fell from 71% before conditioning to 45% after conditioning. The percentage of cells with RRD decreased from 69% to 46%. The changes were accompanied by a 3 mV hyperpolarization of the membrane potentials of the cells and a decrease in baseline activity. After conditioning, increases in excitability were found in cells of the mid thalamus that responded selectively to the click conditioned stimulus (CS) that elicited the conditioned response, and decreases in excitability were found in cells of the posterolateral thalamus that responded to the discriminative acoustic stimulus (DS) to which the animals were trained not to respond. An earlier study showed a potentiation of discharge in response to the CS in units of the midthalamus after similar conditioning and a reduction of the proportion of DS responsive units and peak discharge to the DS in units of the posterolateral thalamus. We conclude that the discharge properties of units of the mid and posterolateral thalamus can change to support discrimination between acoustic stimuli of different functional significance after conditioning.

Chronic deep brain stimulation (DBS) of the periventricular gray (PVG) has been used for the treatment of chronic central pain for decades. In recent years motor cortex stimulation (MCS) has largely supplanted DBS in the surgical management of intractable neuropathic pain of central origin. However, MCS provides satisfactory pain relief in about 50-75% of cases, a range comparable to that reported for DBS (none of the reports are in placebo-controlled studies and hence the further need for caution in evaluating and comparing these results). Our experience also suggests that there is still a role for DBS in the control of central pain. Here we present a series of eight consecutive cases of intractable chronic pain of central origin treated with PVG DBS with an average follow-up of 9 months. In each case, two electrodes were implanted in the PVG and the ventroposterolateral thalamic nucleus, respectively, under guidance of corneal topography/magnetic resonance imaging image fusion. The PVG was stimulated in the frequency range of 2-100 Hz in alert patients while pain was assessed using the McGill-Melzack visual analogue scale. In addition, local field potentials (FPs) were recorded from the sensory thalamus during PVG stimulation. Maximum pain relief was obtained with 5-35 Hz stimulation while 50-100 Hz made the pain worse. This suggests that pain suppression was frequency dependent. Interestingly, we detected low frequency thalamic FPs at 0.2-0.4 Hz closely associated with the pain. During 5-35 Hz PVG stimulation the amplitude of this potential was significantly reduced and this was associated with marked pain relief. At the higher frequencies (50-100 Hz), however, there was no reduction in the FPs and no pain suppression. We have found an interesting and consistent correlation between thalamic electrical activity and chronic pain. This low frequency potential may provide an objective index for quantifying chronic pain, and may hold further clues to the mechanism of action of PVG stimulation. It may be possible to use the presence of these slow FPs and the effect of trial PVG DBS on both the clinical status and the FPs to predict the probable success of future pain control in individual patients.

The distribution in the thalamus of terminal projections from lamina I neurons of the trigeminal, cervical, and lumbosacral dorsal horn was investigated with the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) in the cat. Iontophoretic injections were guided by single- and multi-unit physiological recordings. The injections in particular cases were essentially restricted to lamina I, whereas in others they spread across laminae I-III or laminae I-V. The trigemino- and spinothalamic (TSTT) terminations were identified immunohistochemically. In all cases, regardless of the level of the injections, terminal fibers were consistently distributed in three main locations: the submedial nucleus; the ventral aspect of the basal ventral medial nucleus and ventral posterior nuclei; and, the dorsomedial aspect of the ventral posterior medial nucleus. The terminal fields in the submedial nucleus and the ventral aspect of the ventral posterior group were topographically organized. Terminations along the ventral aspect of the ventral posterior group extended posterolaterally into the caudal part of the posterior nucleus and anteromedially into the ventromedial part of the ventral lateral nucleus. In several cases with trigeminal lamina I injections, a terminal labeling patch was observed within the core of the ventral posterior medial nucleus. In cases with spinal lamina I injections, terminations were also consistently found in the lateral habenula, the parafascicular nucleus, and the nucleus reuniens. Isolated terminal fibers were occasionally seen in the zona incerta, the dorsomedial hypothalamus, and other locations. These anatomical observations extend prior studies of TSTT projections and identify lamina I projection targets that are important for nociceptive, thermoreceptive, and homeostatic processing in the cat. The findings are consistent with evidence from physiological (single-unit and antidromic mapping) and behavioral studies. The novel identification of spinal lamina I input to the lateral habenula could be significant for homeostatic behaviors.

The reciprocal connections between the paraventricular thalamic nucleus (PVT) and the suprachiasmatic nuclei suggest that PVT may participate in the regulation of circadian rhythms. We studied in rats the effect of lesions of the anterior and midposterior regions of the PVT on phase shifts of drinking circadian rhythm induced by light pulses at circadian times 6, 12, and 23, as well as the phase shifts produced by electrical or glutamatergic stimulation of the anterior PVT at the same circadian times. Lesion of the anterior PVT abolishes the advances induced by light during late subjective night, whereas midposterior PVT lesions did not affect the phase shifts. Electrical stimulation or glutamate injections in the anterior PVT mimic the phase-shifting effects of light pulses. These results indicate the participation of the anterior PVT as a modulator of entrainment of circadian rhythms to light.

The thalamic midline and intralaminar nuclei, long thought to be a non-specific arousing system in the brain, have been shown to be involved in separate and specific brain functions, such as specific cognitive, sensory and motor functions. Fundamental to the participation of the midline and intralaminar nuclei in such diverse functions seems to be a role in awareness. It is unknown whether the midline and intralaminar nuclei, together often referred to as the 'non-specific' nuclei of the thalamus, act together or whether each nucleus is involved idiosyncratically in separate circuits underlying cortical processes. Detailed knowledge of the connectivity of each of these nuclei is needed to judge the nature of their contribution to cortical functioning. The present account provides an overview of the results of neuroanatomical tracing studies on the connections of the individual intralaminar and midline thalamic nuclei in the rat, that have been performed over the past decade in our laboratory. The results are discussed together with those reported by other laboratories, and with those obtained in other species. On the basis of the patterns of the afferent and efferent projections, we conclude that the midline and intralaminar thalamic nuclei can be clustered into four groups. Each of the groups can be shown to have its own set of target and input structures, both cortically and subcortically. These anatomical relationships, in combination with functional studies in animals and in humans, lead us to propose that the midline and intralaminar nuclei as a whole play a role in awareness, with each of the groups subserving a role in a different aspect of awareness. The following groups can be discerned: (1) a dorsal group, consisting of the paraventricular, parataenial and intermediodorsal nuclei, involved in viscero-limbic functions; (2) a lateral group, comprising the central lateral and paracentral nuclei and the anterior part of the central medial nucleus, involved in cognitive functions; (3) a ventral group, made up of the reuniens and rhomboid nucleus and the posterior part of the central medial nucleus, involved in multimodal sensory processing; (4) a posterior group, consisting of the centre médian and parafascicular nuclei, involved in limbic motor functions.

The projections from the brainstem to the midline and intralaminar thalamic nuclei were examined in the rat. Stereotaxic injections of the retrograde tracer cholera toxin beta -subunit (CTb) were made in each of the intralaminar nuclei of the dorsal thalamus: the lateral parafascicular, medial parafascicular, central lateral, paracentral, oval paracentral, and central medial nuclei; in the midline thalamic nuclei-the paraventricular, intermediodorsal, mediodorsal, paratenial, rhomboid, reuniens, and submedius nuclei; and, in the anteroventral, parvicellular part of the ventral posterior, and caudal ventral medial nuclei. The retrograde cell body labeling pattern within the brainstem nuclei was then analyzed. Nearly every thalamic site received a projection from the deep mesencephalic reticular, pedunculopontine tegmental, dorsal raphe, median raphe, laterodorsal tegmental, and locus coeruleus nuclei. Most intralaminar thalamic sites were also innervated by unique combinations of medullary and pontine reticular formation nuclei such as the subnucleus reticularis dorsalis, gigantocellular, dorsal paragigantocellular, lateral, parvicellular, caudal pontine, ventral pontine, and oral pontine reticular nuclei; the dorsomedial tegmental, subpeduncular tegmental, and ventral tegmental areas; and, the central tegmental field. In addition, most intralaminar injections resulted in retrograde cell body labeling in the substantia nigra, nucleus Darkschewitsch, interstitial nucleus of Cajal, and cuneiform nucleus. Details concerning the pathways from the spinal trigeminal, nucleus tractus solitarius, raphe magnus, raphe pallidus, and the rostral and caudal linear raphe nuclei to subsets of midline and intralaminar thalamic sites are discussed in the text. The discussion focuses on brainstem-thalamic pathways that are likely involved in arousal, somatosensory, and visceral functions., (Copyright 2002 Wiley-Liss, Inc.)

We have compared the reptilian dorsomedial thalamic nucleus with the mammalian paraventricular thalamic nucleus from a topographic, chemoarchitectonic, and hodological point of view. Both nuclei are localized to a similar position in the dorsalmost aspect of the dorsal thalamus (midline nuclei). They also are uniformly calretinin-immunoreactive, both their cells and neuropil are strongly immunostained for calretinin, and the dorsomedial nucleus presents a strong calbindin immunoreactivity as well. Finally, the reptilian and the mammalian nuclei share a set of afferent and efferent connections with a number of forebrain structures. On the whole, this set of data allows us to propose that the dorsomedial nucleus and the paraventricular thalamic nucleus are homologous. Both represent an important relay station in pathways connecting the hypothalamus with telencephalic areas involved in visceral and motivational aspects of behavior, such as nucleus accumbens and the central amygdala.