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

Abstract

The arginine-vasopressin (AVP)-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs) are known for their role in hydro-electrolytic balance control via their projections to the neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula and other brain regions in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA). The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS), consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptor mRNAs were not detected, using the same method. Water-deprivation (WD) for 24 h, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze (EPM) test, and this effect was mimicked by bilateral microinfusion of AVP into the CeA. Anxious behavior induced by either WD or AVP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of CeA inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.

VGLUT‐VGAT expression delineates functionally specialised populations of vasopressin‐containing neurones including a glutamatergic perforant path‐projecting cell group to the hippocampus in rat and mouse brain

“…We have previously reported that, in the hippocampus and amygdala, there are two types of AVP‐immunopositive fibres: thick ones (with an average thickness of 700‐1000 nm) and thin ones (with an average thickness of 200‐500 nm), distributed and intermingled in selective subfields, with both selectively establishing Gray I and Gray type II synapses preferentially at pyramidal neurones and interneurones, respectively . In the present study, we report an additional observation of a third type that made excitatory synapses onto unidentified hippocampal cellular segments.…”

“…The origin of vasopressin (AVP)‐containing afferents to given limbic regions, including the hippocampus, has been the subject of detailed recent investigations. AVP‐magnocellular neurones of the hypothalamus provide glutamatergic projections to the hippocampus, amygdala, lateral habenula and locus coeruleus . However, we have also reported AVP‐immunopositive fibres in those regions, which are much thinner and make Gray type II synapses.…”

“…These are somatic size (magnocellular vs parvocellular); projection to the neural lobe of the pituitary gland or to the brain; and location of cell bodies either in the classical ‘hormonal’ nuclei of the hypothalamus, such as the PVN, SCN and SON, or within small cell groups at extrahypothalamic locations . Recent findings revealed that the ascending projections of the magnocellular neurosecretory neurones may have profound pro‐motivational and goal‐directed effects projecting monosynaptically to the hippocampus, lateral habenula, amygdala and locus coeruleus in rats under conditions of physiological stress . Yet the role(s) of co‐released classical transmitters in allowing or aiding these profound effects remain understudied, in part because a detailed census of the neurochemistry of these neurones has not been completed.…”

Effects of alcohol and psychostimulants on the vasopressin system: Behavioural implications

“…Acute withdrawal (3 hours and 1 day) after chronic “binge” treatment with cocaine (3 × 15 mg kg ‐1 day ‐1 for 14 days) produced an increase in amygdala AVP mRNA levels; however, this increase did not persist after 10 days of withdrawal . This shows that the effects of cocaine on anxiety‐like behaviours could be the result of an increased anxiety response induced by AVP release in the amygdala …”

The Role of Oxytocin and Vasopressin in Attachment

“…Vasopressin expression may increase following neglect or other negative social experiences in early life (Hernandez et al, 2016;Murgatroyd et al, 2009). We hypothesize that early adversity could also upregulate the vasopressin receptor, especially in brain regions necessary to allow mobilized responses in later life and possibly affecting the capacity to form attachments.…”