Social experience in adolescence shapes prefrontal cortex structure and function in adulthood.

During adolescence, the prefrontal cortex (PFC) undergoes dramatic reorganization. PFC development is profoundly influenced by the social environment, disruptions to which may prime the emergence of psychopathology across the lifespan. We investigated the neurobehavioral consequences of isolation experienced in adolescence in mice, and in particular, the long-term consequences that were detectable even despite normalization of the social milieu. Isolation produced biases toward habit-like behavior at the expense of flexible goal seeking, plus anhedonic-like reward deficits. Behavioral phenomena were accompanied by neuronal dendritic spine over-abundance and hyper-excitability in the ventromedial PFC (vmPFC), which was necessary for the expression of isolation-induced habits and sufficient to trigger behavioral inflexibility in socially reared controls. Isolation activated cytoskeletal regulatory pathways otherwise suppressed during adolescence, such that repression of constituent elements prevented long-term isolation-induced neurosequelae. Altogether, our findings unveil an adolescent critical period and multi-model mechanism by which social experiences facilitate prefrontal cortical maturation.

Persistent behavioral and neurobiological consequences of social isolation during adolescence.

Meaningful social interactions are a fundamental human need, the lack of which can pose serious risks to an individual's physical and mental health. Across species, peer-oriented social behaviors are dramatically reshaped during adolescence, a developmental period characterized by dynamic changes in brain structure and function as individuals transition into adulthood. Thus, the experience of social isolation during this critical developmental stage may be especially pernicious, as it could permanently derail typical neurobiological processes that are necessary for establishing adaptive adult behaviors. The purpose of this review is to summarize investigations in which rodents were isolated during adolescence, then re-housed in typical social groups prior to testing, thus allowing the investigators to resolve the long-term consequences of social adversity experienced during adolescent sensitive periods, despite subsequent normalization of the social environment. Here, we discuss alterations in social, anxiety-like, cognitive, and decision-making behaviors in previously isolated adult rodents. We then explore corresponding neurobiological findings, focusing on the prefrontal cortex, including changes in synaptic densities and protein levels, white matter and oligodendrocyte function, and neuronal physiology. Made more urgent by the recent wave of social deprivation resulting from the COVID-19 pandemic, especially amongst school-aged adolescents, understanding the mechanisms by which even transient social adversity can negatively impact brain function across the lifespan is of paramount importance.

The PI3-Kinase p110ß Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome.

BACKGROUND: The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts. METHODS: Here, we inhibited PI3K p110ß in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type-specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110ß confers resilience to cocaine. RESULTS: Viral-mediated PI3K p110ß silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110ß inhibition restored this ability. Silencing dopamine D2 receptor-expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110ß inhibition restored goal-oriented action. We verified the presence of p110ß in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110ß in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex. CONCLUSIONS: Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110ß provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.

Social Isolation in Adolescence Disrupts Cortical Development and Goal-Dependent Decision-Making in Adulthood, Despite Social Reintegration.

The social environment influences neurodevelopment. Investigations using rodents to study this phenomenon commonly isolate subjects, then assess neurobehavioral consequences while animals are still isolated. This approach precludes one from dissociating the effects of on-going versus prior isolation, hindering our complete understanding of the consequences of social experience during particular developmental periods. Here, we socially isolated adolescent mice from postnatal day (P)31 to P60, then re-housed them into social groups. We tested their ability to select actions based on expected outcomes using multiple reinforcer devaluation and instrumental contingency degradation techniques. Social isolation in adolescence (but not adulthood) weakened instrumental response updating, causing mice to defer to habit-like behaviors. Habit biases were associated with glucocorticoid insufficiency in adolescence, oligodendrocyte marker loss throughout cortico-striatal regions, and dendritic spine and synaptic marker excess in the adult orbitofrontal cortex (OFC). Artificial, chemogenetic stimulation of the ventrolateral OFC in typical, healthy mice recapitulated response biases following isolation, causing habit-like behaviors. Meanwhile, correcting dendritic architecture by inhibiting the cytoskeletal regulatory protein ROCK remedied instrumental response updating defects in socially isolated mice. Our findings suggest that adolescence is a critical period during which social experience optimizes one's ability to seek and attain goals later in life. Age-typical dendritic spine elimination appears to be an essential factor, and in its absence, organisms may defer to habit-based behaviors.

Early-life cocaine interferes with BDNF-mediated behavioral plasticity.

An important aspect of goal-directed action selection is differentiating between actions that are more or less likely to be reinforced. With repeated performance or psychostimulant exposure, however, actions can assume stimulus-elicited-or "habitual"-qualities that are resistant to change. We show that selective knockdown of prelimbic prefrontal cortical Brain-derived neurotrophic factor (Bdnf) increases sensitivity to response-outcome associations, blocking habit-like behavioral inflexibility. A history of adolescent cocaine exposure, however, occludes the "beneficial" effects of Bdnf knockdown. This finding highlights a challenge in treating addiction-that drugs of abuse may bias decision-making toward habit systems even in individuals with putative neurobiological resiliencies.

A review of cyanoacrylate liquid skin protectant and its efficacy on pedal fissures.

INTRODUCTION: Skin fissures are a common dermatologic condition caused by excessive dry skin, numerous systemic diseases, and backless shoe gear. They are defects in skin that fall into the category of damaged, partial-thickness skin wounds, as opposed to full-thickness wounds. Patients with heel fissures are at an increased risk for developing infection, which could cause more severe issues, especially in patients with diabetes and peripheral vascular disease. METHODS: Five patients from Temple Foot and Ankle Institute, Philadelphia, PA, with a total of 8 heel fissures and 2 hallux fissures, were studied. Patients were dispensed 9 vials of a cyanoacrylate liquid skin protectant (Marathon(™), Medline Industries, Inc, Mundelein, IL) to be applied to the fissure every 3 days. Patients returned every 2 weeks for follow-up in clinic. RESULTS: The hallux fissures and 4 of the heel fissures went to complete closure after 2 weeks. There was an average decrease of 1.16 cm in length of the heel fissure dimensions after 2 weeks and an average decrease of 1.1 cm in length of the hallux fissures. CONCLUSION: This novel skin protectant proved to be a comfortable, easy, and effective tool in aiding the resolution of pedal skin fissures.