Interoception and Inflammation in Psychiatric Disorders

Abstract

Despite a historical focus on neurally mediated interoceptive signaling mechanisms, humoral (and even cellular) signals also play an important role in communicating bodily physiological state to the brain. These signaling pathways can perturb neuronal structure, chemistry, and function, leading to discrete changes in behavior. They are also increasingly implicated in the pathophysiology of psychiatric disorders. The importance of these humoral signaling pathways is perhaps most powerfully illustrated in the context of infection and inflammation. Here we provide an overview of how interaction of immune activation of neural and humoral interoceptive mechanisms mediates discrete changes in brain and behavior and highlight how activation of these pathways at specific points in neural development may predispose to psychiatric disorder. As our mechanistic understanding of these interoceptive pathways continues to emerge, it is revealing novel therapeutic targets, potentially heralding an exciting new era of immunotherapies in psychiatry.

Keywords: Autism; Cytokine; Depression; Imaging; Inflammation; Insula; Interoception; Schizophrenia; fMRI.

Figure 1. Peripheral Inflammation activates a neurally mediated interoceptive pathway

Convergent data from diverse imaging techniques show that peripheral inflammation activates a neurally mediated interoceptive pathway projecting to insula. A) Mild pro-inflammatory challenge using the Typhoid vaccine model increases BOLD signal within the human interoceptive brain regions including lateral thalamus (encompassing basal and posterior ventromedial nuclei (VMb and VMpo)) and cortical projections to dorsal mid/posterior and anterior insula within 3 hours of challenge (Modified from 19 with permission). B) LPS-induced peripheral inflammation increases Fluorodeoxyglucose (FDG) uptake with ventrolateral thalamus and posterior and anterior insula within 2 hours of inflammatory challenge (Modified from 18 with permission). C) Mild inflammation (induced using Typhoid vaccination) increases mid/posterior insula FDG-Glucose uptake (lower figure) and magnetization transfer from molecular-bound to free water (upper figure) within 4 hours of inflammatory challenge (Modified from 20 with permission).

Figure 2

‘Circuit’ diagram illustrating visceral, humoral and cellular interoceptive signaling pathways and the major points of interaction

Figure 3. Role of humoral interoceptive pathways in anxiety and depressive-like behavior

A) During homeostatic conditions neuron-derived regulatory factors, such as CX3CL1 and TGFβ maintain microglia in a ‘resting’ state. Low levels of effector monocytes circulate in the blood patrolling for pathogens or tissue damage and a small number of brain macrophages reside in the perivascular space to sample the brain microenvironment. B) During severe psychosocial stress microglia respond to damage-associated molecular patterns (DAMPs) and elevated ATP released from neurons to adopt an ‘activated’ phenotype. Simultaneous increase in sympathetic output results in an increase in circulating monocytes and consequently brain macrophages. These monocytes are believed to traffic to stress-associated brain regions and amplify pro-inflammatory responses through humoral interoceptive pathways involving vascular endothelial IL-1 receptor type-1 signaling. Modified from (145) with permission)