The Bed Nucleus of the Stria Terminalis, Homeostatic Satiety, and Compulsions: What Can We Learn From Polydipsia?

Abstract

A compulsive phenotype characterizes several neuropsychiatric illnesses - including but not limited to - schizophrenia and obsessive compulsive disorder. Because of its perceived etiological heterogeneity, it is challenging to disentangle the specific neurophysiology that precipitates compulsive behaving. Using polydipsia (or non-regulatory water drinking), we describe candidate neural substrates of compulsivity. We further postulate that aberrant neuroplasticity within cortically projecting structures [i.e., the bed nucleus of the stria terminalis (BNST)] and circuits that encode homeostatic emotions (thirst, hunger, satiety, etc.) underlie compulsive drinking. By transducing an inaccurate signal that fails to represent true homeostatic state, cortical structures cannot select appropriate and adaptive actions. Additionally, augmented dopamine (DA) reactivity in striatal projections to and from the frontal cortex contribute to aberrant homeostatic signal propagation that ultimately biases cortex-dependent behavioral selection. Responding becomes rigid and corresponds with both erroneous, inflexible encoding in both bottom-up structures and in top-down pathways. How aberrant neuroplasticity in circuits that encode homeostatic emotion result in the genesis and maintenance of compulsive behaviors needs further investigation.

Keywords: BNST; dopamine; obsessive compulsive disorder; orbitofrontal cortex; schizophrenia.

FIGURE 1

Schedule-induced polydipsia (SIP) protocol. Food restricted rodents are placed into an operant chamber with intermittent pellet delivery (recommended, 1 min interval) and access to water drinking spout. Over 2 h daily SIP sessions, some animals will develop SIP expressed as increased sessional drinking across days; low-drinking animals maintain low levels of water consumption. Daily 22 h homecage drinking during SIP protocol does not differ between high- and low-drinkers. Furthermore, high-drinkers show an adjunctive pattern of drinking during the interpellet interval 60 s, where more time is spent at the drinking spout post-prandial or adjacent to pellet consumption. Adapted with permission from Hawken et al. (2013b).

FIGURE 2

Oval bed nucleus of the stria terminalis (ovBNST) inhibitory plasticity is satiety-state independent in SIP. Adapted with permission from Hawken et al. (2019) and Gardner Gregory (2018). Plasticity at ovBNST GABAergic synapses is caloric-state dependent exhibiting bi-directional plasticity. In a sated state, synapses are biased toward iLTP but when food deprived, they can also express iLTD. When refed, synaptic plasticity quickly returns to iLTP. However, in SIP animals, refeeding does not reinstate iLTP, the mechanism becomes stuck as bidirectional plasticity is lost in animals that show compulsive behaving. iLTP, inhibitory long-term potentiation; iLTD, inhibitory long-term depression; LPI, L-α-lysophosphatidylinositol GPR55 ligand; GPR55, putative cannabinoid receptor; 2-AG, 2-arachidonoylglycerol CB1R ligand; CB1R, cannabinoid receptor.