Barrington's nucleus: a pontine defecation brain area exhibiting prompt and delayed defecation responses.

Abstract

Background & aims: Chronic constipation has attracted considerable attention because of its negative impact on quality of life. While defecation depends on local anorectal motility coordinated by the central nervous system, how it is regulated by the brain remains unclear.

Methods: Brain areas responsible for defecation, known as the defecation brain area (DBA), were identified using a trans-synaptic tracing virus, pseudorabies virus (PRV). Candidate DBAs were assessed using opto- and chemogenetic methods and in vivo monitoring of neural activity.

Results: A significant number of PRV-infected cells were observed in the Barrington's nucleus (Bar), locus coeruleus (LC), ventrolateral periaqueductal gray (vlPAG), and paraventricular hypothalamic nucleus (PVH) following virus infection in the distal colon. Opto- and chemogenetic activation studies revealed that vesicular glutamate transporter 2 (VGluT2) neurons in the Bar and LC, and corticotropin-releasing hormone (CRH) neurons in the Bar exhibit prompt (short-acting) and delayed (long-lasting) contractions in the distal colon, respectively. Their neural activities increased and peaked during spontaneous defecation. In contrast, activation of tyrosine hydroxylase neurons in the LC, which co-express VGluT2, exhibited no response. PRV experiments revealed that PVH^VGluT2 and vlPAG^CRH neurons are upstream neurons that connect to Bar^VGluT2 neurons, and their optogenetic activation resulted in a contraction of the distal colon.

Conclusions: The study is the first to show that the Bar works as the pontine DBA, where Bar^VGluT2 and Bar^CRH neurons exert prompt and delayed defecation activity, respectively. PVH^VGluT2 and vlPAG^CRH neurons are candidates for upstream neurons that regulate defecation through Bar^VGluT2 neurons.