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

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. © 2015 S. Karger AG, Basel.

Patient factors associated with initiation of behavioral weight loss treatment: a prospective observational study in an integrated care setting.

Low enrollment in behavioral weight loss treatments limits their impact. We aimed to identify factors associated with treatment initiation. The participants were outpatients (n = 198) at Veterans Affairs (VA) healthcare facilities who were referred to a free VA-based behavioral weight loss treatment. Participants were assessed on psychosocial factors potentially relevant to treatment initiation. Subsequent treatment initiation was determined via medical record review. Study participants were 77 % male, 60 % African American, and 54 % initiated treatment. In multivariable analyses, treatment initiation was associated with being single, higher anxiety, and patients' perceptions that referring provider supported their weight autonomy. Endorsement of treatment barriers was not associated with treatment initiation. Treatments offering in-person sessions and mood management components were rated as more preferred. Initiation of behavioral weight loss treatments may increase if patients believe that providers respect their weight control autonomy and if healthcare organizations offer treatments that match patients' preferences.

The effect of reduced dopamine D4 receptor expression in the 5-choice continuous performance task: Separating response inhibition from premature responding.

Impairments in attention/vigilance and response disinhibition are commonly observed in several neuropsychiatric disorders. Validating animal models could help in developing therapeutics for cognitive deficits and improving functional outcomes in such disorders. The 5-choice continuous performance test (5C-CPT) in mice offers the opportunity to assess vigilance and two forms of impulsivity. Since reduced dopamine D4 receptor (DRD4) function is implicated in several disorders, DRD4 is a potential therapeutic target for cognition enhancement. We trained wildtype (WT), heterozygous (HT), and knockout (KO) mice of the murine Drd4 to perform the 5C-CPT under baseline and variable stimulus duration conditions. To dissect motor impulsivity (premature responding) from behavioral disinhibition (false alarms), we administered the 5-HT(2C) antagonist SB242084 during an extended inter-trial-interval session. We also examined the preattentive and exploratory profile of these mice in prepulse inhibition (PPI) and the Behavioral Pattern Monitor (BPM). Reduced Drd4 expression in HT mice, as confirmed by quantitative RT-PCR, resulted in response disinhibition and impaired 5C-CPT performance, while premature responding was unaffected. Conversely, SB242084 increased premature responding without affecting response inhibition or attentional measures. No genotypic differences were observed in PPI or BPM behavior. Thus, reduced Drd4 expression impairs attentional performance, but not other behaviors associated with neuropsychiatric disorders. Moreover, the use of signal and non-signal stimuli in the 5C-CPT enabled the differentiation of response disinhibition from motor impulsivity in a vigilance task.

Isolation rearing-induced deficits in contextual fear learning do not require CRF(2) receptors.

Post-weaning social isolation of rodents is used to model developmental stressors linked to neuropsychiatric disorders including schizophrenia as well as anxiety and mood disorders. Isolation rearing produces alterations in emotional memory and hippocampal neuropathology. Corticotropin releasing factor (CRF) signaling has recently been shown to be involved in behavioral effects of isolation rearing. Activation of the CRF(2) receptor is linked to stress-induced alterations in fear learning and may also be involved in long-term adaptation to stress. Here we tested the hypothesis that CRF(2) contributes to isolation rearing effects on emotional memory. At weaning, mice were housed either in groups of three or individually in standard mouse cages. In adulthood, isolation-reared mice exhibited significant reductions in context-specific, but not cue-specific, freezing. Isolation-reared mice exhibited no significant changes in locomotor exploration during brief exposure to a novel environment, suggesting that the reduced freezing in response to context cues was not due to activity confounds. Isolation rearing also disrupted context fear memory in mice with a CRF(2) gene null mutation, indicating that the CRF(2) receptor is not required for isolation effects on fear memory. Thus, isolation rearing disrupts hippocampal-dependent fear learning as indicated by consistent reductions in context-conditioned freezing in two separate cohorts of mice, and these effects are via a CRF(2)-independent mechanism. These findings may be clinically relevant because they suggest that isolation rearing in mice may be a useful model of developmental perturbations linked to disruptions in emotional memory in a variety of neuropsychiatric disorders.