Cognitive effects of subdiaphragmatic vagal deafferentation in rats

Highlights

• Abdominal vagal deafferentation facilitates positively motivated reversal learning.

• Abdominal vagal deafferentation does not affect object recognition memory.

• Abdominal vagal deafferentation does not affect working memory.

Abstract

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.

Introduction

The central nervous system (CNS) constantly receives signals from the viscera via neural and endocrine routes (Mayer, 2011). These signals are part of an interoceptive pathway that can directly and indirectly influence various brain functions such as perception, emotion, and reward- or goal-directed behavior (Critchley & Harrison, 2013). The vagus nerve is one of the key neuronal elements mediating visceral influences on the brain (Berthoud & Neuhuber, 2000). It is the tenth cranial nerve and consists of 80% afferent sensory nerve fibers (Agostoni et al., 1957, Berthoud and Neuhuber, 2000). Vagal afferent neurons synapse bilaterally on the nucleus tractus solitarii (NTS), from where visceral signals are conveyed to various brain stem nuclei and forebrain structures (Barnes et al., 2003, Berthoud and Neuhuber, 2000, Cechetto, 1987, Childs et al., 2015, Khalsa et al., 2009).

Disruption of vagal afferent signaling has been associated with a failure to convey gut-derived signals from the viscera to the CNS (Cryan & Dinan, 2012), which in turn may contribute to changes in mood and affect (George et al., 2003, Groves and Brown, 2005, Klarer et al., 2014). Based on the findings provided by experiments involving vagus nerve stimulation (VNS), it has been suggested that vagal afferents may be an endogenous mediator of certain cognitive functions (Vonck et al., 2014). For example, VNS has been shown to enhance the retention of inhibitory avoidance memory (Clark et al., 1995, Clark et al., 1998) and to facilitate the extinction of conditioned fear (Pena et al., 2013, Pena et al., 2014) in rats. Furthermore, VNS has been found to improve word-recognition memory (Clark, Naritoku, Smith, Browning, & Jensen, 1999) and response selection during action cascading processes (Steenbergen et al., 2015) in human subjects. These cognitive effects have been attributed to modulation of central noradrenergic (NA) and γ-aminobutyric acid (GABA) systems (Beste et al., 2016, Manta et al., 2013, Steenbergen et al., 2015), as well as to neuronal adaptations within limbic and cortical brain areas such as amygdala, hippocampus (HPC), and prefrontal cortex (PFC) (Pena et al., 2014, Zuo et al., 2007).

Some of the reported cognitive effects of VNS, however, remain controversial (Boon et al., 2006, Ogbonnaya and Kaliaperumal, 2013, Vonck et al., 2014), which in turn may undermine current interpretations surrounding the involvement of vagal afferents in cognition. Therefore, we sought to examine the contribution of abdominal vagal afferent signaling to cognitive functions using a rat model of subdiaphragmatic vagal deafferentation (SDA). SDA leads to complete disconnection of all abdominal vagal afferents whilst sparing half of the vagal efferents (Arnold et al., 2006, Norgren and Smith, 1994). To date, it is the most complete and selective vagal deafferentation method for all abdominal visceral fibers and critically differs from total subdiaphragmatic vagotomy (TVX) models, the latter of which leads to a disconnection of both the afferent and efferent fibers of the vagus nerve below the diaphragm (Bercik et al., 2011, Bravo et al., 2011). Unlike TVX (Kraly, Jerome, & Smith, 1986), SDA allows for a discrimination of the relative functional contribution of vagal afferents versus efferents in the absence of severe side effects such as disturbances in gastrointestinal motility and secretion, hypophagia and subsequent body weight loss (Arnold et al., 2006, Azari et al., 2014, Klarer et al., 2014). Based on the reported effects of VNS on working memory (Beste et al., 2016), recognition memory (Clark et al., 1999), and cognitive flexibility (Ghacibeh, Shenker, Shenal, Uthman, & Heilman, 2006a), we compared the performance of SDA and Sham-operated rats in these cognitive domains.