Communal nesting shapes the sex-dependent glutamatergic response to early life stress in the rat prefrontal cortex.

Introduction: Early social environment, either positive or negative, shapes the adult brain. Communal nesting (CN), a naturalistic setting in which 2-3 females keep their pups in a single nest sharing care-giving behavior, provides high level of peer interaction for pups. Early social isolation (ESI) from dam and siblings represents, instead, an adverse condition providing no peer interaction. Methods: We investigated whether CN (enrichment setting) might influence the response to ESI (impoverishment setting) in terms of social behavior and glutamate system in the medial prefrontal cortex (mPFC) of adult and adolescent male and female rats. Results: Pinning (a rewarding component of social play behavior) was significantly more pronounced in males than in females exposed to the combination of CN and ESI. CN sensitized the glutamate synapse in the mPFC of ESI-exposed male, but not female, rats. Accordingly, we observed (i) a potentiation of the glutamatergic neurotransmission in the mPFC of both adolescent and adult males, as shown by the recruitment of NMDA receptor subunits together with increased expression/activation of PSD95, SynCAM 1, Synapsin I and αCaMKII; (ii) a de-recruiting of NMDA receptors from active synaptic zones of same-age females, together with reduced expression/activation of the above-mentioned proteins, which might reduce the glutamate transmission. Whether similar sex-dependent glutamate homeostasis modulation occurs in other brain areas remains to be elucidated. Discussion: CN and ESI interact to shape social behavior and mPFC glutamate synapse homeostasis in an age- and sex-dependent fashion, suggesting that early-life social environment may play a crucial role in regulating the risk to develop psychopathology.

Anorexia-Induced Hypoleptinemia Drives Adaptations in the JAK2/STAT3 Pathway in the Ventral and Dorsal Hippocampus of Female Rats.

Leptin is an appetite-regulating adipokine that is reduced in patients with anorexia nervosa (AN), a psychiatric disorder characterized by self-imposed starvation, and has been linked to hyperactivity, a hallmark of AN. However, it remains unknown how leptin receptor (LepR) and its JAK2-STAT3 downstream pathway in extrahypothalamic brain areas, such as the dorsal (dHip) and ventral (vHip) hippocampus, crucial for spatial memory and emotion regulation, may contribute to the maintenance of AN behaviors. Taking advantage of the activity-based anorexia (ABA) model (i.e., the combination of food restriction and physical activity), we observed reduced leptin plasma levels in adolescent female ABA rats at the acute phase of the disorder [post-natal day (PND) 42], while the levels increased over control levels following a 7-day recovery period (PND49). The analysis of the intracellular leptin pathway revealed that ABA rats showed an overall decrease of the LepR/JAK2/STAT3 signaling in dHip at both time points, while in vHip we observed a transition from hypo- (PND42) to hyperactivation (PND49) of the pathway. These changes might add knowledge on starvation-induced fluctuations in leptin levels and in hippocampal leptin signaling as initial drivers of the transition from adaptative mechanisms to starvation toward the maintenance of aberrant behaviors typical of AN patients, such as perpetuating restraint over eating.

Chronic Lithium Treatment Alters NMDA and AMPA Receptor Synaptic Availability and Dendritic Spine Organization in the Rat Hippocampus.

BACKGROUND: The mechanisms underlying the action of lithium (LiCl) in bipolar disorder(BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities. OBJECTIVE: In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure. RESULTS: We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors. CONCLUSION: Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure.

Recency memory is altered in cocaine-withdrawn adolescent rats: Implication of cortical mTOR signaling.

In humans, cocaine abuse during adolescence poses a significant risk for developing cognitive deficits later in life. Among the regions responsible for cognitive processes, the medial prefrontal cortex (mPFC) modulates temporal order information via mechanisms involving the mammalian-target of rapamycin (mTOR)-mediated pathway and protein synthesis regulation. Accordingly, our goal was to study the effect of repeated cocaine exposure during both adolescence and adulthood on temporal memory by studying the mTOR pathway in the mPFC. Adolescent or adult rats underwent repeated cocaine injections for 15 days and, after two weeks of withdrawal, engaged in the temporal order object recognition (TOOR) test. We found that repeated cocaine exposure during adolescence impaired TOOR performance, while control or adult-treated animals showed no impairments. Moreover, activation of the mTOR-S6-eEF2 pathway following the TOOR test was diminished only in the adolescent cocaine-treated group. Notably, inhibition of the mTOR-mediated pathway by rapamycin injection impaired TOOR performance in naïve adolescent and adult animals, revealing this pathway to be a critical component in regulating recency memory. Our data indicate that withdrawal from cocaine exposure impairs recency memory via the dysregulation of protein translation mechanisms, but only when cocaine is administered during adolescence.

Effects of Multidisciplinary Rehabilitation Enhanced with Neuropsychological Treatment on Post-Acute SARS-CoV-2 Cognitive Impairment (Brain Fog): An Observational Study.

Concentration and memory impairment (named "brain fog") represents a frequent and disabling neuropsychological sequela in post-acute COVID-19 syndrome (PACS) patients. The aim of this study was to assess whether neurocognitive function could improve after a multidisciplinary rehabilitation program enhanced with individualized neuropsychological treatment. A prospective monocentric registry of PACS patients consecutively admitted to our Rehabilitation Unit was created. The Montreal Cognitive Assessment (MoCA) was used to assess cognitive impairment at admission and discharge. A total of sixty-four (64) PACS patients, fifty-six (56) of them with brain fog, were treated with a day-by-day individualized psychological intervention of cognitive stimulation (45 min) on top of a standard in-hospital rehabilitation program. The mean duration of the acute-phase hospitalization was 55.8 ± 25.8 days and the mean in-hospital rehabilitation duration was 30 ± 10 days. The mean age of the patients was 67.3 ± 10.4 years, 66% of them were male, none had a previous diagnosis of dementia, and 66% of the entire sample had experienced severe COVID-19. At admission, only 12% of the patients had normal cognitive function, while 57% showed mild, 28% moderate, and 3% severe cognitive impairment. After psychological treatment, a significant improvement in the MoCA score was found (20.4 ± 5 vs. 24.7 ± 3.7; p < 0.0001) as a result of significant amelioration in the following domains: attention task (p = 0.014), abstract reasoning (p = 0.003), language repetition (p = 0.002), memory recall (p < 0.0001), orientation (p < 0.0001), and visuospatial abilities (p < 0.0001). Moreover, the improvement remained significant after multivariate analysis adjusted for several confounding factors. Finally, at discharge, 43% of the patients with cognitive impairment normalized their cognitive function, while 4.7% were discharged with residual moderate cognitive impairment. In conclusion, our study provides evidence of the effects of multidisciplinary rehabilitation enhanced with neuropsychological treatment on improvement in the cognitive function of post-acute COVID-19 patients.

Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats.

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT-/-) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity.

Long-lasting BDNF signaling alterations in the amygdala of adolescent female rats exposed to the activity-based anorexia model.

Introduction: Anorexia nervosa (AN) is a severe psychiatric disorder characterized by a pathological fear of gaining weight, excessive physical exercise, and emotional instability. Since the amygdala is a key region for emotion processing and BDNF has been shown to play a critical role in this process, we hypothesized that alteration in the amygdalar BDNF system might underline vulnerability traits typical of AN patients. Methods: To this end, adolescent female rats have been exposed to the Activity-Based Anorexia (ABA) protocol, characterized by the combination of caloric restriction and intense physical exercise. Results: The induction of the anorexic phenotype caused hyperactivity and body weight loss in ABA animals. These changes were paralleled by amygdalar hyperactivation, as measured by the up-regulation of cfos mRNA levels. In the acute phase of the pathology, we observed reduced Bdnf exon IX, exon IV, and exon VI gene expression, while mBDNF protein levels were enhanced, an increase that was, instead, uncoupled from its downstream signaling as the phosphorylation of TrkB, Akt, and S6 in ABA rats were reduced. Despite the body weight recovery observed 7 days later, the BDNF-mediated signaling was still downregulated at this time point. Discussion: Our findings indicate that the BDNF system is downregulated in the amygdala of adolescent female rats under these experimental conditions, which mimic the anorexic phenotype in humans, pointing to such dysregulation as a potential contributor to the altered emotional processing observed in AN patients. In addition, since the modulation of BDNF levels is observed in other psychiatric conditions, the persistent AN-induced changes of the BDNF system in the amygdala might contribute to explaining the onset of comorbid psychiatric disorders that persist in patients even beyond recovery from AN.

Motor imagery and action-observation in neurorehabilitation: A study protocol in Parkinson's disease patients.

Introduction: Action Observation Treatment (AOT) and Motor Imagery (MI) represent very promising cognitive strategies in neuro-rehabilitation. This study aims to compare the effectiveness of the two cognitive strategies, taken alone or combined, in Parkinson's disease patients. Material and methods: This study is designed as a prospective randomized controlled trial, with four arms. We estimated a sample size of 64 patients (16 in each treatment group) to be able to detect an effect size of F = 0.4 with a statistical significance of 0.05. Primary outcomes will be functional gains in the FIM and UPDRS scales. Secondary outcome measure will be functional gain as revealed by kinematic parameters measured at Gait Analysis. Discussion: The results of this trial will provide insights into the use of AOT and MI, taken alone or combined, in the rehabilitation of Parkinson's disease patients. Ethics and dissemination: The study protocol was approved by the Ethics Committee of the Don Gnocchi Foundation. The study will be conducted in accordance with the 1996 World Medical Association guidelines and according to good clinical practice. The study has been registered on clinicaltrial.gov under the following code: AOTPRFDG. Dissemination will include both submission of the study to peer-reviewed journals and discussion of the study protocol at conferences.