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.

Dysregulation of Prefrontal Oligodendrocyte Lineage Cells Across Mouse Models of Adversity and Human Major Depressive Disorder Oligodendrocyte dysregulation in mouse models of stress and MDD.

Animal models of adversity have yielded few molecular mechanisms that translate to human stress-related diseases like major depressive disorder (MDD). We congruently analyze publicly available bulk-tissue transcriptomic data from prefrontal cortex (PFC) in multiple mouse models of adversity and in MDD. We apply strategies, to quantify cell-type specific enrichment from bulk-tissue transcriptomics, utilizing reference single cell RNA sequencing datasets. These analyses reveal conserved patterns of oligodendrocyte (OL) dysregulation across animal experiments, including susceptibility to social defeat, acute cocaine withdrawal, chronic unpredictable stress, early life stress, and adolescent social isolation. Using unbiased methodologies, we further identify a dysregulation of layer 6 neurons that associate with deficits in goal-directed behavior after social isolation. Human post-mortem brains with MDD show similar OL transcriptome changes in Brodmann Areas 8/9 in both male and female patients. This work assesses cell type involvement in an unbiased manner from differential expression analyses across animal models of adversity and human MDD and finds a common signature of OL dysfunction in the frontal cortex.

GluN2B inhibition confers resilience against long-term cocaine-induced neurocognitive sequelae.

Cocaine self-administration can disrupt the capacity of humans and rodents to flexibly modify familiar behavioral routines, even when they become maladaptive or unbeneficial. However, mechanistic factors, particularly those driving long-term behavioral changes, are still being determined. Here, we capitalized on individual differences in oral cocaine self-administration patterns in adolescent mice and revealed that the post-synaptic protein PSD-95 was reduced in the orbitofrontal cortex (OFC) of escalating, but not stable, responders, which corresponded with later deficits in flexible decision-making behavior. Meanwhile, NMDA receptor GluN2B subunit content was lower in the OFC of mice that were resilient to escalatory oral cocaine seeking. This discovery led us to next co-administer the GluN2B-selective antagonist ifenprodil with cocaine, blocking the later emergence of cocaine-induced decision-making abnormalities. GluN2B inhibition also prevented cocaine-induced dysregulation of neuronal structure and function in the OFC, preserving mature, mushroom-shaped dendritic spine densities on deep-layer pyramidal neurons, which were otherwise lower with cocaine, and safeguarding functional BLA→OFC connections necessary for action flexibility. We posit that cocaine potentiates GluN2B-dependent signaling, which triggers a series of durable adaptations that result in the dysregulation of post-synaptic neuronal structure in the OFC and disruption of BLA→OFC connections, ultimately weakening the capacity for flexible choice. And thus, inhibiting GluN2B-NMDARs promotes resilience to long-term cocaine-related sequelae.

A molecularly integrated amygdalo-fronto-striatal network coordinates flexible learning and memory.

Behavioral flexibility-that is, the ability to deviate from established behavioral sequences-is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors. However, the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory remain elusive. Here we demonstrate in mice that basolateral amygdala (BLA)→OFC projections bidirectionally control memory formation when familiar behaviors are unexpectedly not rewarded, whereas OFC→dorsomedial striatum (DMS) projections facilitate memory retrieval. OFC neuronal ensembles store a memory trace for newly learned information, which appears to be facilitated by circuit-specific dendritic spine plasticity and neurotrophin signaling within defined BLA-OFC-DMS connections and obstructed by cocaine. Thus, we describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time, whereby novel memories are encoded by BLA→OFC inputs, represented within OFC ensembles and retrieved via OFC→DMS outputs during future choice.

Inter-individual variability amplified through breeding reveals control of reward-related action strategies by Melanocortin-4 Receptor in the dorsomedial striatum.

In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors.

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.

Cell adhesion factors in the orbitofrontal cortex control cue-induced reinstatement of cocaine seeking and amygdala-dependent goal seeking.

Repeated cocaine exposure causes dendritic spine loss in the orbitofrontal cortex, which might contribute to poor orbitofrontal cortical function following drug exposure. One challenge, however, has been verifying links between neuronal structural plasticity and behavior, if any. Here we report that cocaine self-administration triggers the loss of dendritic spines on excitatory neurons in the orbitofrontal cortex of male and female mice (as has been reported in rats). To understand functional consequences, we locally ablated neuronal ß1-integrins, cell adhesion receptors that adhere cells to the extracellular matrix and thus support dendritic spine stability. Degradation of ß1-integrin tone: 1) caused dendritic spine loss; 2) exaggerated cocaine-seeking responses in a cue-induced reinstatement test; and 3) impaired the ability of mice to integrate new learning into familiar routines - a key function of the orbitofrontal cortex. Stimulating Abl-related gene (Arg) kinase, over-expressing Proline-rich tyrosine kinase (Pyk2), and inhibiting Rho-associated coiled-coil containing kinase (ROCK) corrected response strategies, uncovering a ß1-integrin-mediated signaling axis that controls orbitofrontal cortical function. Finally, use of a combinatorial gene silencing/chemogenetic strategy revealed that ß1-integrins support the ability of mice to integrate new information into established behaviors by sustaining orbitofrontal cortical connections with the basolateral amygdala.SIGNIFICANCE STATEMENTCocaine degenerates dendritic spines in the orbitofrontal cortex, a region of the brain involved in interlacing new information into established behaviors. One challenge has been verifying links between cellular structural stability and behavior, if any. In this second of two related investigations, we study integrin family receptors, which adhere cells to the extracellular matrix and thereby stabilize dendritic spines (see also DePoy et al., 2019, Journal of Neuroscience). We reveal that ß1-integrins in the orbitofrontal cortex control food- and cocaine-seeking behaviors. For instance, ß1-integrin loss amplifies cocaine-seeking behavior and impairs the ability of mice to integrate new learning into familiar routines. We identify likely intracellular signaling partners by which ß1-integrins support orbitofrontal cortical function and connectivity with the basolateral amygdala.

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.

Prehabilitative exercise hastens recovery from isoflurane in diabetic and non-diabetic rats.

Diabetes has been demonstrated to be one of the strongest predictors of risk for postoperative delirium and functional decline in older patients undergoing surgery. Exercise is often prescribed as a treatment for diabetic patients and regular physical activity is hypothesized to decrease the risk of postoperative cognitive impairments. Prior studies suggest that anesthetic emergence trajectories and recovery are predictive of risk for later postoperative cognitive impairments. Therapeutic strategies aimed at improving emergence and recovery from anesthesia may therefore be beneficial for diabetic patients. Wistar (n = 32) and Goto-Kakizaki (GK) type 2 diabetic (n = 32) rats between 3-4 months old underwent treadmill exercise for 30 min/day for ten days or remained inactive. Pre-anesthesia spontaneous alternation behavior was recorded with a Y-maze. Rats then received a 2-h exposure to 1.5-2 % isoflurane or oxygen only. The time to reach anesthetic emergence and post-anesthesia recovery behaviors was recorded for each rat. Postsynaptic density protein-95 (PSD-95), an important scaffolding protein required for synaptic plasticity, protein levels were quantified from hippocampus using western blot. Spontaneous alternation behavior (p = 0.044) and arm entries (p < 0.001) were decreased in GK rats. There was no difference between groups in emergence times from isoflurane, but exercise hastened the recovery time (p = 0.008) for both Wistar and GK rats. Following 10 days of exercise, both Wistar and GK rats show increased levels of PSD-95 in the hippocampus. Prehabilitation with moderate intensity exercise, even on a short timescale, is beneficial for recovery from isoflurane in rats, regardless of metabolic disease status.

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.

Endoscopic thoracic sympathectomy for primary focal hyperhidrosis: impact on psycho-social symptomatology and psychotropic medication use.

OBJECTIVES: The tendency for patients with primary focal hyperhidrosis (PFH), characterized by excessive sweating, to experience psycho-social deficits is well documented. In addition, although endoscopic thoracic sympathectomy (ETS) effectively corrects PFH, its role in the psycho-social management of these patients remains unclear. Here, we examined changes in psychiatric symptomatology and psychotropic medication usage in PFH patients following ETS. METHODS: In total, 106 PFH patients underwent ETS and were compared against 213 matched controls. Information on psychiatric diagnosis and prescription was obtained through a retrospective chart review. Prospectively, PFH patients completed Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales to evaluate pre- and postoperative quality-of-life and psycho-social impairment. RESULTS: A significantly greater proportion of PFH patients had been prescribed psychotropic medication (37.7%) compared to controls (14.1%) despite no differences in the proportion of psychiatric diagnoses. Following ETS, 52.5% of the PFH patients who were using psychotropic medications reduced their prescription regimen, compared to only 10% of control patients (P < 0.01). Additionally, scores improved dramatically in each Hyperhidrosis Impact Questionnaires category, and in both the Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales (P < 0.01). CONCLUSIONS: We demonstrate that in over half of PFH patients, psychotropic medication usage was discontinued after ETS, which is consistent with our findings on postoperative improvements in Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales scores. Furthermore, our findings suggest that a considerable proportion of PFH patients who experience psychopathology may be doing so secondary to excessive sweating. Thus, improved awareness or recognition of these associations in the diagnosis and management of PFH patients is warranted.

Bidirectional coordination of actions and habits by TrkB in mice.

Specific corticostriatal structures and circuits are important for flexibly shifting between goal-oriented versus habitual behaviors. For example, the orbitofrontal cortex and dorsomedial striatum are critical for goal-directed action, while the dorsolateral striatum supports habits. To determine the role of neurotrophin signaling, we overexpressed a truncated, inactive form of tropomyosin receptor kinase B [also called tyrosine receptor kinase B (TrkB)], the high-affinity receptor for Brain-derived Neurotrophic Factor, in the orbitofrontal cortex, dorsomedial striatum and dorsolateral striatum. Overexpression of truncated TrkB interfered with phosphorylation of full-length TrkB and ERK42/44, as expected. In the orbitofrontal cortex and dorsomedial striatum, truncated trkB overexpression also occluded the ability of mice to select actions based on the likelihood that they would be reinforced. Meanwhile, in the dorsolateral striatum, truncated trkB blocked the development of habits. Thus, corticostriatal TrkB-mediated plasticity appears necessary for balancing actions and habits.

The role of diffusion tensor imaging in spinal pathology: A review.

Diffusion tensor imaging (DTI) allows for noninvasive, in vivo visualization of white matter fiber tracts in the central nervous system by measuring the diffusion of water molecules. It provides both quantitative and qualitative (i.e., tractography) means to describe a region-of-interest. While protocols for the use of DTI are better established in the brain, the efficacy and potential applications of DTI in spinal cord pathology are less understood. In this review, we examine the current literature regarding the use of DTI in the spinal cord pathology, and in particular its diagnostic and prognostic value in traumatic injury, spinal tumors, cervical myelopathies, amyotrophic lateral sclerosis, and multiple sclerosis. Although structural magnetic resonance imaging (MRI) has long been the gold standard for noninvasive imaging of soft tissues, DTI provides additional tissue characteristics not found in the conventional MRI. We place emphasis on the unique characteristics of DTI, its potential value as an adjunct imaging modality, and its impact on clinical practice.

Role of a Hydrophobic Pocket in Polyamine Interactions with the Polyspecific Organic Cation Transporter OCT3.

Organic cation transporter 3 (OCT3, SLC22A3) is a polyspecific, facilitative transporter expressed in astrocytes and in placental, intestinal, and blood-brain barrier epithelia, and thus elucidating the molecular mechanisms underlying OCT3 substrate recognition is critical for the rational design of drugs targeting these tissues. The pharmacology of OCT3 is distinct from that of other OCTs, and here we investigated the role of a hydrophobic cavity tucked within the translocation pathway in OCT3 transport properties. Replacement of an absolutely conserved Asp by charge reversal (D478E), neutralization (D478N), or even exchange (D478E) abolished MPP(+) uptake, demonstrating this residue to be obligatory for OCT3-mediated transport. Mutations at non-conserved residues lining the putative binding pocket of OCT3 to the corresponding residue in OCT1 (L166F, F450L, and E451Q) reduced the rate of MPP(+) transport, but recapitulated the higher sensitivity pharmacological profile of OCT1. Thus, interactions of natural polyamines (putrescine, spermidine, spermine) and polyamine-like potent OCT1 blockers (1,10-diaminodecane, decamethonium, bistriethylaminodecane, and 1,10-bisquinuclidinedecane) with wild-type OCT3 were weak, but were significantly potentiated in the mutant OCT3s. Conversely, a reciprocal mutation in OCT1 (F161L) shifted the polyamine-sensitivity phenotype toward that of OCT3. Further analysis indicated that OCT1 and OCT3 can recognize essentially the same substrates, but the strength of substrate-transporter interactions is weaker in OCT3, as informed by the distinct makeup of the hydrophobic cleft. The residues identified here are key contributors to both the observed differences between OCT3 and OCT1 and to the mechanisms of substrate recognition by OCTs in general.

Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3.

Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier-mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2), or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [(3)H]MPP(+) uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for [(3)H]spermidine increased more modestly above the background, up to 3-fold. This reflected up to 20-fold lower affinity for spermidine than for MPP(+); thus, K(0.5) for MPP(+) was ~50 µM in OCT1, ~170 µM in OCT2, and ~60 µM in OCT3, whereas for spermidine, K(0.5) was ~1 mM in OCT1, OCT2, and OCT3. J(max) values for MPP(+) and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogues for effect on [(3)H]MPP(+) uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis and aid in the design of polyamine-like OCT-targeted drugs.