Gilbert J. Kirouac

Projections from the paraventricular nucleus of the thalamus to the forebrain, with special emphasis on the extended amygdala

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. J. Comp. Neurol. 506:263–287, 2008.

Orexin (hypocretin) innervation of the paraventricular nucleus of the thalamus.

The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus with projections to limbic forebrain areas such as the nucleus accumbens and amygdala. The orexin (hypocretin) peptides are synthesized in hypothalamic neurons that project throughout the CNS. The present experiments were done to describe the extent of orexin fiber innervation of the PVT in comparison to other midline and intralaminar thalamic nuclei and to establish the location and proportion of orexin neurons innervating the PVT. All aspects of the anteroposterior PVT were found to be densely innervated by orexin fibers with numerous enlargements that also stained for synaptophysin, a marker for synaptic vesicle protein associated with pre-synaptic sites. Small discrete injections of cholera toxin B into the PVT of rats resulted in the retrograde labeling of a relatively small number of orexin neurons in the medial and lateral hypothalamus. The results also showed a lack of topographical organization among orexin neurons projecting to the PVT. Previous studies indicate that orexin neurons and neurons in the PVT appear to be most active during periods of arousal. Therefore, orexin neurons and their projections to the PVT may be part of a limbic forebrain arousal system.

Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats

RationaleAnatomical studies have shown that the paraventricular nucleus of the thalamus (PVT) innervates areas of the forebrain involved in the expression and regulation of emotional behaviors including fear and anxiety. In addition, the PVT is densely innervated by fibers containing orexin-A (OXA) and orexin-B (OXB), peptides that are well-known for their arousal effects on behavior.ObjectivesIn this study, we investigate whether microinjections of orexin receptor agonists and antagonists in the PVT region alter expression of anxiety-like behaviors in the rat as measured in the elevated plus maze.ResultsWe report that microinjections of OXA and OXB in the PVT region elicited anxiety-like response as indicated by a reduction in open arm time and entries. In addition, OXA and OXB produced changes in ethological measures indicative of an anxiety state. Central administrations of antagonists for corticotropin releasing factor (CRF) or the opioid kappa receptors attenuated the anxiogenic effects produced by microinjections of OXA in the PVT region. We also provide evidence that endogenously released orexins act at the PVT to produce anxiety by showing that microinjections of TCSOX229, an orexin-2 receptor antagonist, in the PVT region attenuated the anxiogenic effects produced by a previous exposure to footshock stress.ConclusionsThis study indicates that endogenously released orexins act on the PVT to regulate anxiety levels through mechanisms involving the brain kappa and CRF receptors.

GABAergic Projection from the Ventral Tegmental Area and Substantia Nigra to the Periaqueductal Gray Region and the Dorsal Raphe Nucleus

Previous studies have shown that neurons in the ventral tegmental area (VTA) and substantia nigra (SN) project to the ventrolateral periaqueductal gray (PAGvl) and dorsal raphe nucleus (DR). Research has also shown that stimulation of neurons in the VTA/SN elicits cardiovascular depressor responses that are mediated by a projection to the PAGvl/DR. Anatomic and physiological experiments were done in the present study to determine the neurochemical identity of the VTA/SN projection to the PAGvl/DR. Experiments were done to characterize the origin and chemical nature of this projection by combining cholera toxin B tracing with immunofluorescence for the 67K isoform of glutamic acid decarboxylase (GAD) and tyrosine hydroxylase. The PAGvl/DR region was found to receive a substantial input from neurons in the VTA, SN, and deep mesencephalic nucleus. The DR was preferentially innervated by neurons in the VTA, whereas the PAGvl was preferentially innervated by neurons in the SN. A proportion of neurons in the VTA and the reticular portion of the SN found to project to the PAGvl/DR were GAD positive. In addition, experiments were done in urethane‐anesthetized rats to determine whether injections of a γ‐aminobutyric acid (GABA) antagonist in the region of the PAGvl/DR attenuated the cardiovascular depressor responses produced by glutamate stimulation of the VTA/SN. Injections of the GABA‐blocking agent picrotoxin (2.5 nmol, 500 nl) into the PAGvl/DR eliminated the cardiovascular responses from stimulation of the VTA/SN (0.01 M, 50 nl). The results of the present investigation provide evidence for a GABAergic projection from the VTA/SN to the PAGvl/DR. This projection may be an important regulator of the PAGvl/DR, an area of the midbrain involved in the production of behavioral and physiological responses to pain and stress. J. Comp. Neurol. 469:170–184, 2004.

Functional and anatomical connection between the paraventricular nucleus of the thalamus and dopamine fibers of the nucleus accumbens.

The shell of the nucleus accumbens (NacSh) receives a dense innervation from dopamine (DA) neurons in the ventral tegmental area (VTA) and from glutamate neurons in the paraventricular nucleus of the thalamus (PVT). The present study examined in urethane‐anesthetized rats the effects of electrical stimulation of the PVT on DA levels in the NacSh as measured with amperometry and chronoamperometry. Stimulation of the PVT (40 Hz, 1.0 ms, 400 μA, 5 seconds) resulted in a brief increase in electrochemical currents detected in the NacSh. Inhibition of DA neurons in the VTA using lidocaine (4%, 500 nL) or intravenous apomorphine (0.15 mg/kg) decreased the resting voltammetric signal but had no effect on PVT‐evoked responses. Blocking of ionotropic glutamate receptors in the NacSh with local administration of kynurenic acid attenuated the PVT‐evoked responses. Anterograde tracing with biotinylated dextran amine demonstrated that PVT targets regions of very dense tyrosine hydroxylase fiber staining in the NacSh. Consistent with the projection pattern of the PVT to the NacSh, stimulation of the PVT evoked the largest oxidation current changes in the NacSh, whereas small or no changes were elicited in other areas of the striatum. This study suggests that glutamate release from PVT terminals can act on ionotropic glutamate receptors in the NacSh to induce DA efflux. Modulation of DA levels in the NacSh by the PVT may be linked to arousal‐induced increases in DA tone and could be involved in the facilitation of specific behavioral patterns associated with arousal or stressful situations. J. Comp. Neurol. 500:1050–1063, 2007.

Sources of inputs to the anterior and posterior aspects of the paraventricular nucleus of the thalamus.

The paraventricular nucleus of the thalamus (PVT) is part of a group of midline and intralaminar thalamic nuclei implicated in arousal and attention. Recent research points to anatomical and functional differences between the anterior (aPVT) and posterior PVT (pPVT). The present study re-examines the main sources of brain inputs to the aPVT and pPVT in the rat following iontophoretic injections of the retrograde tracer cholera toxin B (CTb) in the PVT. The location and the number of retrogradely labeled neurons in different regions of the brain were examined to determine which brain areas are likely to exert a strong influence on the aPVT and pPVT. The largest number of labeled neurons was found in layer 6 of the prelimbic, infralimbic and posterior insular cortices following injections in the pPVT. In contrast, the largest number of labeled neurons following injections of CTb in the aPVT was found to be in the hippocampal subiculum and the prelimbic cortex. Other areas of the brain including the reticular nucleus of the thalamus, periaqueductal gray, parabrachial nucleus and dorsomedial nucleus of the hypothalamus were found to contain a more moderate number of neurons following injections of CTb in either the aPVT or pPVT. The results of the present tracing study clearly show that more neurons in the prefrontal cortex and subiculum project to the PVT than neurons from the hypothalamus and brainstem. These results highlight the potential importance of top–down modulation of PVT mechanisms and behavioral functions.

Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood.

The purpose of this review is to describe how the function and connections of the paraventricular thalamic nucleus (Pa) may play a role in the regulation of stress and negative emotional behavior. Located in the dorsal midline thalamus, the Pa is heavily innervated by serotonin, norepinephrine, dopamine (DA), corticotropin-releasing hormone, and orexins (ORX), and is the only thalamic nucleus connected to the group of structures comprising the amygdala, bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAcc), and infralimbic/subgenual anterior cingulate cortex (sgACC). These neurotransmitter systems and structures are involved in regulating motivation and mood, and display abnormal functioning in several psychiatric disorders including anxiety, substance use, and major depressive disorders (MDD). Furthermore, rodent studies show that the Pa is consistently and potently activated following a variety of stressors and has a unique role in regulating responses to chronic stressors. These observations provide a compelling rationale for investigating the Pa in the link between stress and negative emotional behavior, and for including the Pa in the neural pathways of stress-related psychiatric disorders.

Placing the paraventricular nucleus of the thalamus within the brain circuits that control behavior

This article reviews the anatomical connections of the paraventricular nucleus of the thalamus (PVT) and discusses some of the connections by which the PVT could influence behavior. The PVT receives neurochemically diverse projections from the brainstem and hypothalamus with an especially strong innervation from peptide producing neurons. Anatomical evidence is also presented which suggests that the PVT relays information from neurons involved in visceral or homeostatic functions. In turn, the PVT is a major source of projections to the nucleus accumbens, the bed nucleus of the stria terminalis and the central nucleus of the amygdala as well as the cortical areas associated with these subcortical regions. The PVT is activated by conditions and cues that produce states of arousal including those with appetitive or aversive emotional valences. The paper focuses on the potential contribution of the PVT to circadian rhythms, fear, anxiety, food intake and drug-seeking. The information in this paper highlights the potential importance of the PVT as being a component of the brain circuits that regulate reward and defensive behavior with the hope of generating more research in this relatively understudied region of the brain.

Innervation of the paraventricular nucleus of the thalamus from cocaine- and amphetamine-regulated transcript (CART) containing neurons of the hypothalamus

The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus with heavy projections to the nucleus accumbens and other limbic regions. Previous studies have shown that the PVT contains fibers immunoreactive for cocaine‐ and amphetamine‐related transcript (CART). The purpose of the present study was to determine the location of CART neurons innervating the PVT of the rat by using retrograde tracing with cholera toxin B (CTb) combined with immunofluorescence for CTb and CART (amino acid sequence 55–102). Immunohistochemical analysis of CART in the dorsal thalamus showed that the PVT is densely innervated by CART fibers whereas adjacent midline and intralaminar thalamic nuclei are unlabeled. Injections of CTb in the dorsal midline thalamus retrogradely labeled neurons in several areas of the hypothalamus and brainstem which also contained CART neurons. The largest number of double‐labeled neurons (CTb/CART) was found in the arcuate nucleus of the hypothalamus. CTb/CART neurons were also found in the lateral hypothalamus, zona incerta, and periventricular hypothalamus. These results indicate that the arcuate nucleus is a major source of CART fibers in the PVT. CART neurons in the arcuate nucleus monitor circulating hormonal signals and may regulate food intake and hypothalamic‐pituitary‐adrenal (HPA) activity. Consequently, CART neurons in the arcuate nucleus may transmit signals to the PVT which in turn may influence limbic regions involved in regulating food intake and the HPA. J. Comp. Neurol. 497:155–165, 2006.

Changes in emotional behavior produced by orexin microinjections in the paraventricular nucleus of the thalamus.

The paraventricular nucleus of the midline thalamus (PVT) innervates areas of the extended amygdala known to play a key role in the expression of emotional behaviors. In this study, microinjections of orexins (hypocretins), which have excitatory actions on neurons in the PVT, in the midline thalamus were used to investigate if the PVT modulates the expression of emotional behavior in the open field. First, the approach-avoidance tendency (number and duration of visit to the center area) associated with novelty was examined in orexin treated rats before and after placing a novel object in the center of the open field. Second, the expression of ethological behaviors (rearing, locomotion, freezing, and grooming) in the open field was used to determine the effects of orexins on emotionality. Microinjections of orexin-A (OXA) or orexin-B (OXB) in the PVT decreased exploration of the center area and the novel object indicating that the center area and the object had more aversive properties in orexin treated rats. Both OXA and OXB microinjections in the PVT increased the expression of freezing and grooming behaviors which are indicative of a negative emotional state. The results indicate that microinjections of orexins in the PVT made the test situation more aversive and produced avoidance behaviors. This suggests that orexins may act at the PVT to modulate behaviors associated with a negative emotional state.