Thirst Is Associated with Suppression of Habenula Output and Active Stress Coping: Is there a Role for a Non-canonical Vasopressin-Glutamate Pathway?

Abstract

Water-homeostasis is a fundamental physiological process for terrestrial life. In vertebrates, thirst drives water intake, but the neuronal circuits that connect the physiology of water regulation with emotional context are poorly understood. Vasopressin (VP) is a prominent messenger in this circuit, as well as L-glutamate. We have investigated the role of a VP circuit and interaction between thirst and motivational behaviors evoked by life-threatening stimuli in rats. We demonstrate a direct pathway from hypothalamic paraventricular VP-expressing, glutamatergic magnocellular neurons to the medial division of lateral habenula (LHbM), a region containing GABAergic neurons. In vivo recording and juxtacellular labeling revealed that GABAergic neurons in the LHbM had locally branching axons, and received VP-positive axon terminal contacts on their dendrites. Water deprivation significantly reduced freezing and immobility behaviors evoked by innate fear and behavioral despair, respectively, accompanied by decreased Fos expression in the lateral habenula. Our results reveal a novel VP-expressing hypothalamus to the LHbM circuit that is likely to evoke GABA-mediated inhibition in the LHbM, which promotes escape behavior during stress coping.

Hypothalamic Vasopressinergic Projections Innervate Central Amygdala GABAergic Neurons: Implications for Anxiety and Stress Coping

“…A significant body of literature implicates AVP as a transmitter subserving stress responses in adult rodents without a history of stressor exposure, and in adult rodents with a history of stressor exposure during early post-natal life (Veenema and Neumann, 2008; Zhang et al, 2010, 2012, 2016; Zhang and Hernández, 2013; Hernández et al, 2015). A potential linkage between these two AVP-related types of stress response is found in the observations that early-life stress, in rats, leads to reorganization of vasopressinergic neurons of the PVN (Zhang et al, 2012).…”

Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving

“…Aside from the peptides, LHb neurons are reported to be mainly glutamatergic, expressing either vesicular glutamate transporter 2 (Geisler et al, 2007; Brinschwitz et al, 2010) or vesicular glutamate transporter 3 (Herzog et al, 2004). A small subset of LHb neurons expresses GAD67 (Brinschwitz et al, 2010; Zhang et al, 2016), thereby synthesizing GABA, but there is as yet no confirmation that LHb GAD-expressing neurons also contain vesicular GABA transporter (VGaT), the vesicular machinery that packages GABA into synaptic vesicles for synaptic release.…”

“…For example, anterograde tracing verifies projections to LHb from the dorsomedial nucleus (Thompson et al, 1996) and from vasopressin-expressing neurons in the medial parvicellular part of the paraventricular nucleus (Sofroniew and Weindl, 1984). More recently, Hernandez et al (2015) have provided additional compelling evidence in favor of a PVN-LHb pathway and have gone on to show that it exerts potent behavioral effects due presumably to actions of vasopressin in the LHb (Zhang et al, 2016, see also below). Another vasopressin-expressing projection to the LHb, from parvocellular neurons in the suprachiasmatic nucleus, has been reported in rats (Buijis et al, 1978; Sofroniew and Weindl, 1978) and primates (Sofroniew et al, 1981) and was supported by one anterograde tracing study (Alonso et al, 1986).…”

An emerging role for the lateral habenula in aggressive behavior

“…Conversely, nearly all of the of the neurons in the LHb are glutamatergic and possess long-ranging axons that target both midbrain and brainstem regions (Wiess and Veh 2011, Li et al 2011, Aizawa et al 2012, Lammel et al 2012, Stamatakis and Stuber 2012). Interestingly, only small numbers of local inhibitory neurons have been described in the LHb, and they are primarily located in the medial aspect of the LHb (Smith et al 1987, Zhang et al 2016). For the purpose of this review, we will focus the exclusively on how LHb circuits mediate aggression and reward–related behavior.…”