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

Abstract

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.

Keywords: addiction; anxiety; depression; orexin; paraventricular; stress; subgenual; thalamus.

Figure 1

The paraventricular nucleus of the thalamus (Pa) in nonhuman primates. The Pa is a small group of densely-packed neurons in the dorsal midline thalamus. Shown here are three adjacent coronal sections through the dorsal midline thalamus of the Macaca fascicularis stained for (A) Nissl, (B) AChE, and (C) myelin. The Pa is densely stained with AChE but is relatively lightly stained for myelin. Other thalamic nuclei shown are the anterodorsal (AD), anteromedial (AM), anteroventral (AV), and parataenial (Pt) nuclei. The stria medullaris (sm) is also shown. Scale bar = 500 µm. Adapted from Hsu and Price (2007)

Figure 2

Contributions of the Pa in psychiatric disorders. Rodent studies suggest a role for the Pa in anxiety, drug relapse, and regulating the effects of chronic stress. (A) Orexin (ORX) projections from the hypothalamus to the Pa regulate fear and anxiety-like behavior through the central nucleus of the amygdala (CeA), and bed nucleus of the stria terminalis (BNST). (B) In a pathway for drug relapse, ORX and cocaine- and amphetamine-related transcript (CART) from the hypothalamus, and contextual cues from the subiculum project to the Pa. In turn, the Pa regulates dopamine (DA) efflux in the nucleus accumbens shell (NAccSh) and drug-seeking behavior. (C) Via the CeA and BNST, the Pa has been shown to be an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress. A few studies in rodent models of depression have shown involvement of the Pa, however its specific role in depressive-like behavior remains to be determined. The role of the Pa in regulating chronic stress may also influence (A) and (B). There is likely significant overlap between the pathways for these disorders, which are highly comorbid, and are exacerbated by severe or chronic stress. MDD, major depressive disorder; sgACC, subgenual anterior cingulate cortex.

Figure 3

Summary of Pa connections linking stress with motivation and mood. The connections shown here in the human brain are based on rodent and nonhuman primate studies. Structures in the midbrain (periaqueductal gray, PAG; dorsal raphe, DR; locus coeruleus, LC; parabrachial nucleus, PB) send stress signals to the Pa, which in turn may influence activity in the agranular insular (AI) cortex, central (CeA) and basolateral (BLA) nuclei of the amygdala, nucleus accumbens shell (NAccSh), bed nucleus of the stria terminalis (BNST), and subgenual anterior cingulate cortex (sgACC), all of which are implicated in major depressive, substance use, and anxiety disorders. Other connections with the Pa include the entorhinal cortex/subiculum (EC/S), dorsomedial (DM) hypothalamus, and suprachiasmatic nucleus (SCN). Heavy input to the Pa by serotonin, norepinephrine, dopamine, corticotropin-releasing hormone, ORX, and endogenous opioids may regulate this pathway and determine how stressors, particularly chronic stressors, influence motivation and mood. Inset shows area of detail in the human brain. Adapted from Hsu and Price (2009).