Consequences of chronic ethanol exposure on cognitive and motor functions are widely studied due to the neurodegeneration that ethanol produces in the cerebellum and other brain areas, including some corticolimbic regions. However, there is scarce information about the structural neuroplasticity effects of chronic ethanol exposure that ultimately lead to characteristic neurodegenerative consequences. For this purpose, we evaluated the effects of chronic ethanol exposure in adult male rats on exploratory behavior (locomotor activity induced by a novel environment) and structural neuroplasticity in corticolimbic and cerebellar neurons. After 90 days of ad libitum ethanol (10%) exposure, the locomotor behavior of the animals did not differ from that of the control group (exposed to water). Structural neuroplasticity was assessed using the Golgi-Cox technique in neurons from corticolimbic areas and the cerebellum. The findings revealed that ethanol exposure induced basilar dendritic atrophy without modifying the dendritic spine density in pyramidal cells in prefrontal cortex layers 3 and 5, the CA1 region of the dorsal hippocampus, and the basolateral amygdala. In contrast, ethanol exposure hypotrophied the dendritic arbor of Purkinje cells and reduced the density of dendritic spines in these cells. These data contribute to the knowledge of the neuroplasticity-related mechanisms underlying the neurodegenerative consequences of chronic ethanol exposure and its cognitive implications.

The endocannabinoid (eCB) system has been proposed as a potential target for developing new medications for opioid use disorder (OUD). However, the status of the eCB system, specifically brain cannabinoid receptor type 1 (CB1R) in OUD, is unknown. In this study, CB1R availability was measured in males with OUD on stable opioid agonist treatment (OAT) (n = 10) versus healthy controls (HC) (n = 18), using High-Resolution Research Tomography (HRRT) and the CB1R-specific radiotracer, [11C]OMAR. The average volume of distribution (VT) across 13 regions was compared between the OUD and HC groups. Average VT was 15% lower in OUD vs. HC subjects (p = 0.04). Lower VT in OUD compared to HC was also observed in several corticolimbic areas. Within OUD no effects on CB1R availability were observed for treatment medication (methadone vs. buprenorphine), current stress levels, or antidepressant medication. No associations between the average VT and duration of OAT treatment or time since the last illicit opioid use were observed. This preliminary study suggests lower CB1R availability in men with OUD. Larger studies are necessary to replicate these findings. Future research should also draw from a more heterogeneous population, particularly by incorporating females, to better assess the potential confounding and moderating clinical factors. If confirmed, the observed alterations in CB1R availability in OUD may provide a rationale for targeting the eCB system in the treatment of OUD.

Apathy, characterized by diminished goal-directed behaviors, frequently occurs in patients with Parkinson's disease (PD). The dopamine-releasing neurons of the ventral tegmental area (VTA) have been closely related to this behavioral disruption and project widely to the corticolimbic areas, yet their functional and structural connectivity in regard to other brain regions remain unknown in patients with PD and pure apathy (PD-PA). This study thus aimed to characterize the alterations of functional connectivity (FC) of the VTA and white matter structural connectivity in PD-PA. In this study, 29 patients with PD-PA, 37 with PD but not pure apathy (PD-NPA), and 28 matched healthy controls (HCs) underwent T1-weighted, resting state functional magnetic resonance imaging, and diffusion tensor imaging scans. Patients of this cross-sectional retrospective study were consecutively recruited from The First Affiliated Hospital of Nanjing Medical University between April 2017 and October 2021. Meanwhile, HCs were consecutively recruited from the local community and the Health Examination Center of our hospital. An analysis of covariance and a general linear model were respectively conducted to investigate the functional and structural connectivity among three groups. The tract-based spatial statistics (TBSS) approach was used to investigate the white matter structural connectivity. Patients with PD-PA showed reduced FC of the VTA with the left medial superior frontal gyrus (SFGmed) when compared to the patients with PD-NPA [t=-3.67; voxel-level P<0.001; cluster-level family-wise error-corrected P (PFWE)<0.05]. Relative to the HCs, patients with PD-PA demonstrated reduced FC of the VTA with the left SFGmed (t=-4.98; voxel-level P<0.001; cluster-level PFWE<0.05), right orbital superior frontal gyrus (SFGorb) (t=-5.08; voxel-level P<0.001; cluster-level PFWE<0.05), and right middle frontal gyrus (MFG) (t=-5.08; voxel-level P<0.001; cluster-level PFWE<0.05). Moreover, the reductions in VTA FC with the left SFGmed were associated with severe apathy symptoms in patients with PD-PA (r=-0.600; P=0.003). However, a TBSS approach did not reveal any significant differences in fiber tracts between the three groups. This study identified reduced FC within the mesocortical network (VTA-SFGmed) of patients with PD-PA. These findings may provide valuable information for administering neuromodulation therapies in the alleviation of apathy symptoms in those with PD.

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague-Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy.

Reduced corticolimbic habituation to negative stimuli characterizes bipolar depressed suicide attempters

The antidepressant effect of subanesthetic doses of ketamine was recognized 20 years ago. This review briefly summarizes the current understanding of the antidepressant mechanisms and the available clinical research on the use of racemic ketamine and enantiomer esketamine for depression. The antidepressant effect of subanesthetic doses of ketamine is currently considered to be predominantly mediated by improved neuroplasticity in cortico-limbic areas in the brain. Single dose of 0.5 mg/kg of ketamine infused intravenously over 40 min, or single intranasal dose of esketamine cause rapid antidepressant and antisuicidal effects within hours of administration, and the antidepressant effect may last up to a week. Repeated administration of nasal spray esketamine is considered to prevent relapse of depression. Longitudinal studies are currently insufficient. When used in various doses for anesthetic induction for electroconvulsive therapy, ketamine improves seizure quality and may possibly diminish posttherapy cognitive impairment. A rapid onset antidepressive effect of ketamine and esketamine has been proven conclusively. The results of extensive basic science research of the mechanism of action of low-dose ketamine doses has led to an alternative hypothesis of the pathophysiology of depression and the development of a novel neurotrophic concept of depression. Further longitudinal studies are warranted to determine the safety and efficacy of repeated administration of ketamine and its analogs to prevent relapse and recurrence of depression.

Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.

Antidepressant drugs in adolescent depression are sometimes mired by efficacy issues and paradoxical effects. Transcranial direct current stimulation (tDCS) could represent an alternative. We tested the antidepressant action of prefrontal tDCS and paroxetine (20 mg/kg, intraperitoneal) in olfactory bulbectomised (OBX) adolescent rats. Using enzyme-linked immunosorbent assays and in situ hybridisation, we examined treatment-induced changes in plasma brain-derived neurotrophic factor (BDNF) and brain serotonin transporter (SERT) and 5-HT-1A mRNA. OBX-induced anhedonia-like reductions in sucrose preference (SP) correlated with open field (OF) hyperactivity. These were accompanied by decreased zif268 mRNA in the piriform/amygdalopiriform transition area, and increased zif268 mRNA in the hypothalamus. Acute paroxetine (2 days) led to a profound SP reduction, an effect blocked by combined tDCS-paroxetine administration. Chronic (14 days) tDCS attenuated hyperlocomotion and its combination with paroxetine blocked OBX-induced SP reduction. Correlations among BDNF, SP and hyperlocomotion scores were altered by OBX but were normalised by tDCS-paroxetine co-treatment. In the brain, paroxetine increased zif268 mRNA in the hippocampal CA1 subregion and decreased it in the claustrum. This effect was blocked by tDCS co-administration, which also increased zif268 in CA2. tDCS-paroxetine co-treatment had variable effects on 5-HT1A receptors and SERT mRNA. 5-HT1A receptor changes were found exclusively within depression-related parahippocampal/hippocampal subregions, and SERT changes within fear/defensive response-modulating brainstem circuits. These findings point towards potential synergistic efficacies of tDCS and paroxetine in the OBX model of adolescent depression via mechanisms associated with altered expression of BDNF, 5-HT1A, SERT and zif268 in discrete corticolimbic areas.

Elucidation of the mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor-expressing neurons leading to acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK→Egr-1/Zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons of NAc slices; and in either male or female mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the NAc in adult mice, using adeno-associated virus-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-medium spiny neurons and cocaine-induced behaviors, including locomotor sensitization and conditioned place preference. Abrogation of NCS-Rapgef2 gene expression in mPFC and BLA, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase IIα promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1 receptor-expressing neurons in the NAc, but not in corticolimbic areas, contributes to cocaine-induced locomotor sensitization and conditioned place preference. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling.SIGNIFICANCE STATEMENT ERK phosphorylation in dopamine D1 receptor-expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioral adaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the NAc is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequent enhanced locomotor response and drug seeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-medium spiny neurons encode the experience of psychomotor stimulant exposure.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women in reproductive age and is associated with reproductive, endocrine, metabolic, cardiovascular, and psychological outcomes. All these disorders are thought to be affected by central mechanisms which could be a major contributor in pathogenesis of PCOS. This mini-review discusses the relevance of central nervous system imaging modalities in understanding the neuroendocrine origins of PCOS as well as their relevance to understanding its comorbidities. Current data suggest that central nervous system plays a key role in development of PCOS. Decreased global and regional brain volumes and altered white matter microstructure in women with PCOS is shown by structural imaging modalities. Functional studies show diminished reward response in corticolimbic areas, brain glucose hypometabolism, and greater opioid receptor availability in reward-related regions in insulin-resistant patients with PCOS. These structural and functional disturbances are associated with nonhomeostatic eating, diminished appetitive responses, as well as cognitive dysfunction and mood disorders in women with PCOS. Structural and functional brain imaging is an emerging modality in understanding pathophysiology of metabolic disorders such as diabetes and obesity as well as PCOS. Neuroimaging can help researchers and clinicians for better understanding the pathophysiology of PCOS and related comorbidities as well as better phenotyping PCOS.

Autistic traits lie on a continuously distributed spectrum ranging from non-clinical to clinical conditions. Indeed, autistic traits have been observed in general population at sub-threshold levels. Here, the main aim was to investigate differences in resting state (RS) electroencephalographic (EEG) power spectrum in individuals with high vs. low autistic traits. Fifty undergraduates completed the Autism-Spectrum Quotient (AQ) and the Empathy Quotient (EQ). For each participant five minutes of RS-EEG were recorded and analysed by means of the exact Low-Resolution Electromagnetic Tomography software (eLORETA). A Two-Step Cluster Analysis revealed two groups: high autistic traits (AT+) and low autistic traits (AT−) group. Compared to AT−, AT+ individuals showed an increase of delta power in parietal/occipital and cortico-limbic areas. No alterations were observed in other frequency bands. Furthermore, both AQ and EQ total scores were positively correlated with delta EEG power after controlling for sex, age, and subclinical psychopathological traits. Results show that AT+ individuals exhibit an increase in slow RS EEG power in regions involved in self-referential processes, suggesting a reduction in these internally directed mental activities and adding new evidence on the existence of a continuum in the autistic spectrum which spreads from clinical to non-clinical significance.

Restricted intermittent food access to palatable food (PF) induces addiction-like behaviors and plastic changes in corticolimbic brain areas. Intermittent access protocols normally schedule PF to a fixed time, enabling animals to predict the arrival of PF. Because outside the laboratory the presence of PF may occur in a random unpredictable manner, the present study explored whether random access to PF would stimulate similar addiction-like responses as observed under a fixed scheduled. Rats were randomly assigned to a control group without chocolate access, to ad libitum access to chocolate, to fixed intermittent access (CH-F), or to random unpredictable access (CH-R) to chocolate. Only the CH-F group developed behavioral and core temperature anticipation to PF access. Both groups exposed to intermittent access to PF showed binge eating, increased effort behaviors to obtain chocolate, as well as high FosB/ΔFosB in corticolimbic areas. Moreover, FosB/ΔFosB in all areas correlated with the intensity of binge eating and effort behaviors. We conclude that both conditions of intermittent access to PF stimulate addiction-like behaviors and FosB/ΔFosB accumulation in brain reward areas; while only a fixed schedule, which provides a time clue, elicited anticipatory activation, which is strongly associated with craving behaviors and may favor relapse during withdrawal.

Altered brain levels of arachidonic acid-derived inflammatory eicosanoids in a rodent model of anorexia nervosa

ABSTRACT Objectives: One factor contributing to the development of obesity is overeating palatable food. The palatability of food is driven by specific energy yielding combinations and flavor profiles that may contribute to its overconsumption. In rodents, restricted access to palatable food (PF) is a strong stimulus to trigger binge-type eating behavior (BTE), food anticipatory activity (FAA), effort behaviors and withdrawal symptoms. This is accompanied by plastic changes in corticolimbic areas associated with motivation and reward responses. Palatable food contains mainly a mixture of fat and sugar, thus, the contribution of each macronutrient for the behavioral and neuronal changes is unclear. Methods: In this study, Wistar rats were exposed to restricted access to 50% fat rich diet (FRD) or 50% sugar rich diet (SRD) in order to compare the intensity of BTE, FAA, effort behaviors and withdrawal responses. Results: In corticolimbic areas, c-Fos activation and ΔFosB accumulation were evaluated. After an acute exposition, rats ate more SRD than FRD, but FDR stimulated higher c-Fos. After chronic administration, the FDR group exhibited higher levels of BTE and FAA; this was associated with higher c-Fos and accumulation of ΔFosB in the corticolimbic system. Similar effects in the FRD group were observed after one week of withdrawal. Discussion: Present data indicate that the fat rich diet is a stronger stimulus than the sugar rich diet for the development of wanting behavior for reward and the underlying plastic changes in the corticolimbic system. The differential effects may be due to the differing caloric density of the diets.

Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine

To evaluate the influence of acute restraint stress (ARS) on plasma enkephalinase and oxytocinase activities. ARS modifies basal activities in cortico-limbic regions of rats and induces changes in the correlations observed between these regions. The interactions between plasma and cortico-limbic activities will be also evaluated. Enkephalinase (AlaAP and LeuAP) and oxytocinase (P-LeuAP) activities were fluorometrically determined in plasma of control and stressed rats using aminoacyl-β-naphthylamides (aaNNap), AlaNNap and LeuNNap as substrates. No differences in enzymatic activities were observed between control and stressed animals in plasma. In contrast, highly significant positive and negative correlations between plasma and cortico-limbic regions were demonstrated in controls. Stress conditions significantly alter the pattern of these correlations. The present results clearly support a connection between plasma and brain involving certain neuropeptidase activities that change under stress conditions.

Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/serotonin transporter ligand (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. We found that Parkinson patients had lower (123)I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error-corrected P value of less than 0.05. Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease.

The recent literature on anorexia nervosa (AN) suggests that functional and structural abnormalities of cortico-limbic areas might play a role in the evolution of the disease. We explored global and regional brain volumes in a cross-sectional and follow-up study on adolescents affected by AN. Eleven adolescents with AN underwent a voxel-based morphometry study at time of diagnosis and immediately after weight recovery. Data were compared to volumes carried out in eight healthy, age and sex matched controls. Subjects with AN showed increased cerebrospinal fluid volumes and decreased white and gray matter volumes, when compared to controls. Moreover, significant regional gray matter decrease in insular cortex and cerebellum was found at time of diagnosis. No regional white matter decrease was found between samples and controls. Correlations between psychological evaluation and insular volumes were explored. After weight recovery gray matter volumes normalized while reduced global white matter volumes persisted.

Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression

Early Life Stress and Trauma and Enhanced Limbic Activation to Emotionally Valenced Faces in Depressed and Healthy Children