At the heart of the interoception network: Influence of the parasubthalamic nucleus on autonomic functions and motivated behaviors

Highlights

• The parasubthalamic nucleus is embedded in neural circuits mediating interoception and emotions.

• Parasubthalamic neurons are excitatory and express stress-related neuropeptides.

• The parasubthalamic nucleus responds to food ingestion, visceral distress, and aversive memories.

• The parasubthalamic nucleus controls cardiovascular function, thermoregulation, feeding, and impulsivity.

• Recruitment of parasubthalamic neurons may contribute to negative urgency.

Abstract

The parasubthalamic nucleus (PSTN), a small nucleus located on the lateral edge of the posterior hypothalamus, has emerged in recent years as a highly interconnected node within the network of brain regions sensing and regulating autonomic function and homeostatic needs. Furthermore, the strong integration of the PSTN with extended amygdala circuits makes it ideally positioned to serve as an interface between interoception and emotions. While PSTN neurons are mostly glutamatergic, some of them also express neuropeptides that have been associated with stress-related affective and motivational dysfunction, including substance P, corticotropin-releasing factor, and pituitary adenylate-cyclase activating polypeptide. PSTN neurons respond to food ingestion and anorectic signals, as well as to arousing and distressing stimuli. Functional manipulation of defined pathways demonstrated that the PSTN serves as a central hub in multiple physiologically relevant networks and is notably implicated in appetite suppression, conditioned taste aversion, place avoidance, impulsive action, and fear-induced thermoregulation. We also discuss the putative role of the PSTN in interoceptive dysfunction and negative urgency. This review aims to synthesize the burgeoning preclinical literature dedicated to the PSTN and to stimulate interest in further investigating its influence on physiology and behavior.

This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Introduction

Organisms maintain their physiology and adapt to changing internal and external environments through homeostatic mechanisms driven by the nervous system. Central processing of bottom-up, afferent signals from the viscera, a process known as interoception, permits detection of changes (conscious or subconscious) within the body, which in turn generates top-down regulatory directives aiming to achieve homeostatic equilibrium (Craig, 2004; Critchley et al., 2004). Accordingly, vital functions such as feeding and drinking rely on interoceptive information to motivate behavior towards homeostasis.

Bodily sensations are conveyed to the brain through neural (vagus nerve, spinothalamic tract) and humoral (via circumventricular organs) channels, which, for the most part, converge in the nucleus of the tractus solitarius (NTS). The information then transits through the parabrachial nuclei (PBN), periaqueductal gray matter (PAG), and viscerosensory thalamus. The latter structures then relay the signals to the hypothalamus, amygdala, anterior cingulate cortex, and agranular insular cortex (AI), where they get integrated with other sensory modalities and learned associations, and ultimately modulate emotional states and behavioral choices (Critchley and Harrison, 2013; Khalsa et al., 2018). Hypothalamic cell groups coordinate the feedback regulation of autonomic functions in response to those signals through their projections to preganglionic sympathetic and parasympathetic neurons in the medulla (e.g., NTS) and spinal cord (Loewy, 1991).

The parasubthalamic nucleus (PSTN) was identified 17 years ago as a preautonomic hypothalamic nucleus (Goto and Swanson, 2004) and it has since emerged as a heavily interconnected node within the central network sensing and regulating autonomic function (Fig. 1). The present review aims to synthesize the growing preclinical work that has revealed the connectivity and molecular makeup of PSTN neurons and their engagement not only in the regulation of autonomic functions but also in the control of feeding behavior and the encoding of aversive experiences. The PSTN is still by and large an understudied brain region (as an index, a Pubmed search using the keyword “parasubthalamic” currently returns 30 publications) and we hope that this review will stimulate interest in further investigating its multifaceted effects on physiology and behavior.