Role of abdominal vagal afferents in the gut-brain axis: visceral influences on centrally mediated behaviors

Abstract

The central nervous system (CNS) and viscera are engaged in continuous bidirectional communication. This functional relationship is often referred to as the “gut-brain axis” and allows “top-down” (CNS to viscera) and “bottom-up” (viscera to CNS) information flow. The gut-brain axis is not only crucial for gastrointestinal homeostasis, but is likely to have various effects on affect, motivation, and higher cognitive functions. The vagus nerve (VN), consisting of 80% afferent sensory fibers, represents a key neuronal element in the bidirectional gut-brain axis. In addition to its parasympathetic contribution, the VN is essential in conveying visceral signals to the brain by synapsing bilaterally on the nucleus tractus solitarii (NTS), from where visceral signals can be transferred to various brain stem nuclei and forebrain structures. Abnormal VN functions have frequently been associated with psychiatric disorders such as depression and schizophrenia and have attained growing clinical relevance by the recent use of chronic vagus nerve stimulation (VNS) for treatment-resistant epilepsy and depression. Despite the recognition of the VN in this pathological context, however, only little is known regarding the relative involvement of vagal afferents in modulating behavioral functions relevant in psychiatric disorders. The work presented in this thesis aimed at addressing the latter by exploring various behavioral phenotypes in a preclinical rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date. The first series of experiments revealed that disrupted vagal afferent signaling modifies brain and behavioral functions relevant to schizophrenia and related psychotic disorders. More specifically, it was found that SDA leads to brain transcriptional changes in functional networks related to schizophrenia, causes impairments in sensorimotor gating and the attentional control of associative learning, increases the sensitivity to the dopamine-stimulating drug, amphetamine, and elevates basal dopamine levels in the nucleus accumbens. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions. The second series of experiments aimed at exploring the involvement of afferent vagal signaling in cognition, with a primary emphasis on cognitive functions previously shown to be modulated by VNS. While the overall effect of SDA on cognitive function seems limited, we could demonstrate that cognitive flexibility is subjected to visceral modulation through abdominal vagal afferents. Finally, a third series of experiments examined the effects of SDA on affective behaviors implicated in depression and related mood disorders. The main rationale underlying these experiments was based on the findings provided by recent clinical studies that tentatively suggest an anti-depressant effect of VNS. Consistent with the later notion, we found that loss of abdominal vagal afferents by SDA induces depression-like behavioral impairments, including behavioral despair and anhedonia. Thus, abdominal vagal afferents may indeed play a pathophysiological role in depression and related mood disorders. Overall, the work presented in this thesis provides evidence that disruption of abdominal vagal afferent signaling is able to change various behavioral and (to a lesser extent) cognitive functions, many of which are strongly implicated in major psychiatric disorders such as schizophrenia and depression. Thus, the findings presented in this thesis emphasize the possibility that the disruption of afferent vagal signaling may be relevant for the pathophysiology of these disorders. The presented findings also support the hypothesis that modulating vagal afferent signaling may be a valuable approach in the development of novel (non-pharmacological) therapeutic strategies for the treatment of major psychiatric disorders. Future investigations of the possible links between SDA, gut-derived signals, and ascending vagal neurotransmission may thus help to gain more in-depth insights into the intricate mechanisms whereby visceral signals can influence complex brain and behavioral functions relevant to psychiatric disorders.