Inborn differences in emotional behavior coincide with alterations in hypothalamic paraventricular motor projections

Abstract

Integrated behavioral responses to emotionally salient stimuli require the concomitant activation of descending neural circuits that integrate physiological, affective, and motor responses to stress. Our previous work interrogated descending circuits in the brainstem and spinal cord that project to motor and sympathetic targets. The hypothalamic paraventricular nucleus (PVN), a key node of this circuitry, integrates multiple motor and sympathetic responses activated by stress. The present study sought to determine whether descending projections from the PVN to targets in muscle and adrenal gland are differentially organized in rats with inborn differences in emotionality and stress responsivity. We utilized retrograde transsynaptic tract‐tracing with unique pseudorabies virus (PRV) recombinants that were injected into sympathectomized gastrocnemius muscle and adrenal gland in two rat models featuring inborn differences in emotional behavior. Our tract‐tracing results revealed a significant decrease in the number of PVN neurons with poly‐synaptic projections to the gastrocnemius in male Wistar Kyoto [WKY] rats (versus Sprague Dawley rats) and selectively bred Low Novelty Responder [bLR] rats (versus selectively bred High Novelty Responder [bHR] rats). These neuroanatomical differences mirrored behavioral observations showing that both WKY and bLR rats display marked inhibition of emotional motor responses in a variety of settings relative to their respective controls. Our findings suggest that, in male rodents, PVN poly‐synaptic projections to skeletal muscle may regulate emotional motor and coping responses to stress. More broadly, perturbations in PVN motor circuitry may play a role in mediating psychomotor disturbances observed in depression or anxiety‐related disorders.

Premotor projections from the locus coeruleus and periaqueductal grey are altered in two rat models with inborn differences in emotional behavior

“…Consistent with our group’s prior work, the first experiment employed retrograde viral tract-tracing to label premotor and presympathetic efferents in a cohort of WKY and Sprague Dawley rats ( n = 9 per strain) as performed previously (Shupe et al 2021 ). To this end, two transgenic recombinants of an attenuated PRV strain, PRV-Bartha, were used: (1) PRV-152, which contains the gene encoding enhanced green fluorescent protein (eGFP), and (2) PRV-BaBlu, which carries the lac Z gene at the gG locus and codes for β-galactosidase (β-gal) (Kim et al 1999 ; Smith et al 2000 ).…”

“…The process of generating and characterizing the selectively bred HR and LR lines has been described elsewhere (Stead et al 2006 ; Flagel et al 2014 ). Validation of the emotional behavior phenotypes in these strains was performed previously (Shupe et al 2021 ). Housing was maintained under conditions of standard temperature (21–23 °C) and humidity (50–55%) in a 12:12 h light–dark cycle (lights on at 6:00 a.m.).…”

“…To this end, two transgenic recombinants of an attenuated PRV strain, PRV-Bartha, were used: (1) PRV-152, which contains the gene encoding enhanced green fluorescent protein (eGFP), and (2) PRV-BaBlu, which carries the lac Z gene at the gG locus and codes for β-galactosidase (β-gal) (Kim et al 1999 ; Smith et al 2000 ). In the present study, PRV-152 was injected into sympathectomized gastrocnemius muscle (i.e., skeletal muscle; selected motor target) while PRV-BaBlu was injected into the adrenal gland (i.e., selected sympathetic target) as described in earlier work by our laboratory (Kerman et al 2006 , 2007 ; Kerman 2008 ; Shupe et al 2021 ). Due to technical challenges related to the β-gal primary antibody as well as practical consideration of the lack of differences in immunolabeling of presympathetic connections previously recorded in the PVN (Shupe et al 2021 ), analyses in the present study were limited to immunolabeling of eGFP-expressing premotor-connected cells.…”

“…In the present study, PRV-152 was injected into sympathectomized gastrocnemius muscle (i.e., skeletal muscle; selected motor target) while PRV-BaBlu was injected into the adrenal gland (i.e., selected sympathetic target) as described in earlier work by our laboratory (Kerman et al 2006 , 2007 ; Kerman 2008 ; Shupe et al 2021 ). Due to technical challenges related to the β-gal primary antibody as well as practical consideration of the lack of differences in immunolabeling of presympathetic connections previously recorded in the PVN (Shupe et al 2021 ), analyses in the present study were limited to immunolabeling of eGFP-expressing premotor-connected cells.…”

“…Perturbations of the stress response are commonly observed in patients with mood and anxiety disorders (Nestler et al 2002 ; Tafet and Nemeroff 2020 ). Recent work by our laboratory investigated whether somatomotor-sympathetic circuitry of the PVN, an key integrator of behavioral, endocrine, and autonomic responses to stress (Herman and Cullinan 1997 ), is altered in rodent models with emotional behavior dysregulation (Shupe et al 2021 ). Our PRV-mediated neuroanatomical investigations in male Wistar-Kyoto (WKY) and selectively bred Low Novelty Responder (bLR) rats, two models featuring inborn differences in emotionality and stress reactivity (Stead et al 2006 ; Stedenfeld et al 2011 ; Nam et al 2014 ; Burke et al 2016 ; Prater et al 2017 ), revealed that both strains display fewer descending somatomotor projections from the PVN, potentially contributing to the locomotor disturbances associated with their altered emotional states (Shupe et al 2021 ).…”