Abdominal vagal deafferentation alters affective behaviors in rats.

BACKGROUND: There is growing evidence for a role of abnormal gut-brain signaling in disorders involving altered mood and affect, including depression. Studies using vagus nerve stimulation (VNS) suggest that the disruption of vagal afferent signaling may contribute to these abnormalities. To test this hypothesis, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on affective behaviors. METHODS: SDA- and Sham-operated male rats were subjected to several tests that are commonly used in preclinical rodent models to assess the presence of anhedonic behavior, namely the novel object-induced exploration test, the novelty-suppressed eating test, and the sucrose preference test. In addition, we compared SDA and Sham rats in a social interaction test and the forced swim test to assess sociability and behavioral despair, respectively. RESULTS: Compared to Sham controls, SDA rats consistently displayed signs of anhedonic behavior in all test settings used. SDA rats also showed increased immobility and reduced swimming in the forced swim test, whereas they did not differ from Sham controls with regards to social approach behavior. LIMITATIONS: This study was conducted in male rats only. Hence, possible sex-specific effects of SDA on affective behaviors remained unexamined. CONCLUSIONS: Our findings demonstrate that hedonic behavior and behavioral despair are subject to visceral modulation through abdominal vagal afferents. These data are compatible with preclinical models and clinical trials showing beneficial effects of VNS on depression-like and affective behaviors.

Abdominal Vagal Afferents Modulate the Brain Transcriptome and Behaviors Relevant to Schizophrenia.

Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions.SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions.

Cognitive effects of subdiaphragmatic vagal deafferentation in rats.

Vagal afferents are a crucial neuronal component of the gut-brain axis and mediate the information flow from the viscera to the central nervous system. Based on the findings provided by experiments involving vagus nerve stimulation, it has been suggested that vagal afferent signaling may influence various cognitive functions such as recognition memory and cognitive flexibility. Here, we examined this hypothesis using a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective abdominal vagal deafferentation method existing to date. We found that SDA did not affect working memory in a nonspatial alternation task, nor did it influence short-, intermediate-, and long-term object recognition memory. SDA did also not affect the acquisition of positively reinforced left-right discrimination learning, but it facilitated the subsequent reversal left-right discrimination learning. The SDA-induced effects on reversal learning emerged in the absence of concomitant changes in motivation towards the positive reinforcer, indicating selective effects on cognitive flexibility. Taken together, these findings suggest that the relative contribution of vagal afferent signaling to cognitive functions is limited. At the same time, our study demonstrates that cognitive flexibility, at least in the domains of positively reinforced learning, is subjected to visceral modulation through abdominal vagal afferents.

Gut vagal afferents differentially modulate innate anxiety and learned fear.

Vagal afferents are an important neuronal component of the gut-brain axis allowing bottom-up information flow from the viscera to the CNS. In addition to its role in ingestive behavior, vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear. Here, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on innate anxiety, conditioned fear, and neurochemical parameters in the limbic system. We found that compared with Sham controls, SDA rats consistently displayed reduced innate anxiety-like behavior in three procedures commonly used in preclinical rodent models of anxiety, namely the elevated plus maze test, open field test, and food neophobia test. On the other hand, SDA rats exhibited increased expression of auditory-cued fear conditioning, which specifically emerged as attenuated extinction of conditioned fear during the tone re-exposure test. The behavioral manifestations in SDA rats were associated with region-dependent changes in noradrenaline and GABA levels in key areas of the limbic system, but not with functional alterations in the hypothalamus-pituitary-adrenal grand stress. Our study demonstrates that innate anxiety and learned fear are both subjected to visceral modulation through abdominal vagal afferents, possibly via changing limbic neurotransmitter systems. These data add further weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior.