Repeated Binge Drinking Increases Perineuronal Nets in the Insular Cortex

Abstract

Background Alcohol exposure leads to changes in the extracellular matrix (ECM) in the brain, which profoundly impacts neuronal plasticity. Perineuronal nets (PNs) are specialized ECM structures that enclose subpopulations of neurons in the cortex. Adolescent exposure to alcohol induces long-lasting increases in the expression of PN components in the cortex in adult mice. However, it has not been determined whether binge alcohol exposure in young adults alters PNs. Here, we examined PNs and their core components in the insula and primary motor cortex after repeated binge-like ethanol consumption in adult mice. Methods The 4 day drinking in the dark (DID) procedure was performed in mice for 1 or 6 weeks to model binge alcohol consumption. The impact of ethanol drinking on PNs was examined by fluorescent staining of brain sections using a marker for PNs, Wisteria floribunda agglutinin (WFA). In another set of experiments, cortex was dissected and Western blots and quantitative real-time PCR (qPCR) were performed to evaluate the expression of the PN proteins aggrecan, brevican, and phosphacan. Results Binge-like ethanol drinking for 6 weeks caused a significant increase in PNs in the insula, as measured by WFA binding. Aggrecan, brevican and phosphacan protein expression, and aggrecan mRNA expression, were also elevated in the insula after 6 weeks of ethanol drinking. In contrast, expression of PN components did not change after 1 week of DID. The increase in PNs appears to be specific to the insula, since alterations were not observed in the primary motor cortex. Conclusions Our results provide the first evidence that insular PNs increase after long-term binge drinking. The insula mediates compulsive alcohol use. Since PNs influence neuronal firing and plasticity, increased PNs in the insula after multiple binge cycles may contribute to restricted neuronal plasticity and lead to the development of compulsive alcohol use.

Signals from the Fourth Dimension Regulate Drug Relapse

“…Binge-like ethanol drinking in mice increases PNNs and elevates expression of CSPGs aggrecan, brevican, and phosphacan in the insula, but not anterior cingulate or primary motor cortex [91]. In the OFC, PNNs and CSPGs brevican and neurocan are elevated in adult mice exposed to alcohol during adolescence [92].…”

Involvement of the cerebellum in cocaine-induced memory

“…Coleman and colleagues (2014) found that binge-like ethanol exposure in adolescent mice induced an increase in PNN expression in orbitofrontal cortex (OFC) when mice reached adulthood. This effect was also observed in young adult mice under similar experimental conditions (Chen et al, 2015). Furthermore, a cocaine-sensitizing regimen decreased PNN expression in the medial nucleus of the cerebellum (Vazquez-Sanroman et al, 2015a).…”

Weaving a Net of Neurobiological Mechanisms in Schizophrenia and Unraveling the Underlying Pathophysiology

“…Previous research conducted across a variety of animal species (i.e., rhesus monkey (43, 44), bison (45), dog (46), gerbil (47), guinea pig (48), zebra finch (49), rat (38), and mouse (25, 50-56)) has shown PNNs to be widely distributed in the brain. Similarly, in humans, PNNs have been found to be present in a variety of brain regions, including entorhinal cortex (28), amygdala (28, 29, 57), hippocampus (58), motor and somatosensory cortex (59), visual cortex (27) and prefrontal cortex (27), all regions (bar the visual cortex) which have been reported to be affected in schizophrenia (60).…”

“…Given that PNN-encapsulated neurons are prevalent throughout the limbic system (28, 29, 76) and PNNs are capable of modulating receptors (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA receptors) known to be integral for learning and memory (77), these structures have been considered to play an important role in memory formation (54), which may include emotional memory (51, 55) in addition to reward-related memory (50, 78). In fact, it has been reported that PNNs are involved in long-term potentiation (LTP) and long-term depression (LTD) in hippocampal slices, as these physiological events are impaired following enzymatic degradation of CSPGs, or removal of TN-R (79, 80).…”

“…The presence of PNNs in the striatum (52), olfactory pathway (38, 76), basal ganglia (82), cerebellum (83), thalamus (56), visual cortex (27), insular cortex (50), high vocal center (49), orbital cortex (53), central auditory pathway (43, 84, 85), and spinal cord (86) suggests that the regulatory effects of PNNs are involved in a wide range of brain functions, including motor coordination, olfaction, procedural learning, voluntary motor movement, arousal state, vision, integration of cognitive, affective, sensory and autonomic information, vocal development, mediating decision making, processing of auditory stimuli, and nociception, respectively. Indeed, depletion or alterations in the molecular composition of PNNs induced by enzyme degradation (such as chondroitinase ABC, ChABC), by knock-out methods, or by clinical disease processes are associated with anomalies in sensory perception (67), impaired vision (71) as well as altered gait (52).…”