Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats

Abstract

Cognitive impairments appear early in the progression of schizophrenia, often preceding the symptoms of psychosis. Thus, the systems subserving these functions may be more vulnerable to, and mechanistically linked with, the initial pathology. Understanding the trajectory of behavioral and anatomical abnormalities relevant to the schizophrenia prodrome and their sensitivity to interventions in relevant models will be critical to identifying early therapeutic strategies. Isolation rearing of rats is an environmental perturbation that deprives rodents of social contact from weaning through adulthood and produces behavioral and neuronal abnormalities that mirror some pathophysiology associated with schizophrenia, e.g. frontal cortex abnormalities and prepulse inhibition (PPI) of startle deficits. Previously, we showed that PPI deficits in isolation-reared rats emerge in mid-adolescence (4 weeks after weaning; approx. postnatal day 52) but are not present when tested at 2 weeks after weaning (approx. postnatal day 38). Because cognitive deficits are reported during early adolescence, are relevant to the prodrome, and are linked to functional outcome, we examined the putative time course of reversal learning deficits in isolation-reared rats. Separate groups of male Sprague Dawley rats were tested in a two-choice discrimination task at 2 and 8 weeks after weaning, on postnatal day 38 and 80, respectively. The isolation-reared rats displayed impaired reversal learning at both time points. Isolation rearing was also associated with deficits in PPI at 4 and 10 weeks after weaning. The reversal learning deficits in the isolated rats were accompanied by reductions in parvalbumin immunoreactivity, a marker for specific subpopulations of GABAergic neurons, in the hippocampus. Hence, isolation rearing of rats may offer a unique model to examine the ontogeny of behavioral and neurobiological alterations that may be relevant to preclinical models of prodromal psychosis.

Disruption of behavior and brain metabolism in artificially reared rats

“…That is, during rat infancy or in adolescence (Semple et al, ). After‐weaning models have many possibilities from a single isolation (Pournajafi‐Nazarloo et al, ; Powell et al, ), to several days or weeks. The main observed effect is anxiety, but there are reductions in neuronal activity measured through Fos expression (Lukkes et al, ; Wall et al, ; Ahern et al, ), dendritic growth (Silva‐Gómez et al, ), electrical activity, and neurotransmitters release (Cinini et al, ; Soga et al, ; Sargin et al, ; Murínová et al, ).…”

Modeling neurodevelopmental cognitive deficits in tasks with cross‐species translational validity

“…Impaired reversal learning as measured by trials to criterion on a two-choice discrimination task has also been observed in isolation-reared mice (Schrijver et al 2004) and rats (Powell et al 2015). Reversal learning deficits appeared in early adolescence (postweaning day 38) and persisted into adulthood [day 80 (Powell et al 2015)].…”

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

“…Impaired PPI has also been described in children of alcoholics (Grillon et al, 1997, 2000), heavy drinkers (Hutchison et al, 2003), and abstinent alcoholics (Marin et al, 2012). In aSI rats, PPI deficits have been observed immediately postisolation (Ko and Liu, 2015; Liu et al, 2011; Powell et al, 2015) and well into adulthood, even when aGH rats were then isolated as adults (McCool and Chappell, 2009). …”