Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

Abstract

Anxiety disorders are highly prevalent in modern society and better treatments are required. Key brain areas and signaling systems underlying anxiety include prefrontal cortex, hippocampus, and amygdala, and monoaminergic and peptidergic systems, respectively. Hindbrain GABAergic projection neurons that express the peptide, relaxin‐3, broadly innervate the forebrain, particularly the septum and hippocampus, and relaxin‐3 acts via a Gi/o‐protein‐coupled receptor known as the relaxin‐family peptide 3 receptor (RXFP3). Thus, relaxin‐3/RXFP3 signaling is implicated in modulation of arousal, motivation, mood, memory, and anxiety. Ventral hippocampus (vHip) is central to affective and cognitive processing and displays a high density of relaxin‐3‐positive nerve fibers and RXFP3 binding sites, but the identity of target neurons and associated effects on behavior are unknown. Therefore, in adult, male rats, we assessed the neurochemical nature of hippocampal RXFP3 mRNA‐expressing neurons and anxiety‐like and social behavior following chronic RXFP3 activation in vHip by viral vector expression of an RXFP3‐selective agonist peptide, R3/I5. RXFP3 mRNA detected by fluorescent in situ hybridization was topographically distributed across the hippocampus in somatostatin‐ and parvalbumin‐mRNA expressing GABA neurons. Chronic RXFP3 activation in vHip increased anxiety‐like behavior in the light–dark box and elevated‐plus maze, but not the large open‐field test, and reduced social interaction with a conspecific stranger. Our data reveal disruptive effects of persistent RXFP3 signaling on hippocampal GABA networks important in anxiety; and identify a potential therapeutic target for anxiety disorders that warrants further investigation in relevant preclinical models.

Acetylcholine Muscarinic Receptors in Ventral Hippocampus Modulate Stress-Induced Anxiety-Like Behaviors in Mice

“…Previous studies found that ventral hippocampal neurons control anxiety by their projection to medial prefrontal cortex (mPFC), lateral septum, and lateral hypothalamic area. The vHPC modulates anxiety-like behavior through influencing neuronal activities (Tu et al, 2014;Fisher et al, 2017;Rytova et al, 2019). In our experiments, chronic stress induced anxiety-like behaviors and enhanced neuronal activities in vHPC in mice.…”

“…A previous study found that amygdala-vHPC glutamatergic projection could bidirectionally modulate mouse SI (Felix-Ortiz and Tye, 2014). Moreover, relaxin-3 receptor on GABA neurons in rat vHPC modulates mouse social avoidance (Rytova et al, 2019). Interestingly, our study found that intra-vHPC injection of scopolamine and knockdown of M1 mAChRs in the vHPC can attenuate CRS mouse social avoidance.…”

Enhanced Glutamatergic Currents at Birth in Shank3 KO Mice

“…Furthermore, even though the hippocampus is primarily known for its modulation of spatial navigation and episodic memory, studies have also shown that this structure processes information relative to affective and motivated behaviors [60, 61]. Interestingly, amygdala inputs projecting towards the ventral hippocampus can modulate social behaviors [62], while the activation of the relaxin-3 receptor in the ventral hippocampus results in increased anxiety behaviors and social avoidance [63]. Thus, alterations in anxiety and social interaction behaviors reported in studies using Shank3 −/− mice [45, 64, 65] might be due in part to an impairment in hippocampal activity, and evaluating developmental alterations during the first weeks of life in this structure could shed some light into the underlying mechanisms of this phenotype.…”

Targeted viral vector transduction of relaxin-3 neurons in the rat nucleus incertus using a novel cell-type specific promoter

“…As such, relaxin-3 signalling, likely working in conjunction with co-expressed, fast-acting GABA neurotransmission (Ma et al, 2007), appears to promote arousal, in part through the selective disinhibition of key neural networks (Ma et al, 2018). One such network, the septohippocampal pathway, contains inhibitory, parvalbumin-positive medial septal neurons and hippocampal somatostatin- and parvalbumin-positive interneurons that express RXFP3 in rat and mouse brain (Haidar et al, 2017; Albert-Gasco et al, 2018a; Rytova et al, 2019; Haidar et al, 2019). Selective blockade or deletion of RXFP3 (Ma et al, 2009a; Haidar et al, 2017, 2019) in these regions impairs spatial memory and associated hippocampal theta rhythm, to which relaxin-3 NI neurons are strongly phase-locked (Ma et al, 2013).…”

“…Selective blockade or deletion of RXFP3 (Ma et al, 2009a; Haidar et al, 2017, 2019) in these regions impairs spatial memory and associated hippocampal theta rhythm, to which relaxin-3 NI neurons are strongly phase-locked (Ma et al, 2013). Social recognition is also influenced by relaxin-3 signalling, as RXFP3 agonists, delivered by viral vector-mediated expression in ventral hippocampus (Rytova et al, 2019) or intracerebroventricular infusion (Albert-Gasco et al, 2018b), reduce interactions of rats with novel conspecifics.…”