Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice.

Basolateral amygdala (BLA) is a key hub for affect in the brain,1,2,3 and dysfunction within this area contributes to a host of psychiatric disorders.4,5 BLA is extensively and reciprocally interconnected with frontal cortex,6,7,8,9 and some aspects of its function are evolutionarily conserved across rodents, anthropoid primates, and humans.10 Neuron density in BLA is substantially lower in primates compared to murine rodents,11 and frontal cortex (FC) is dramatically expanded in primates, particularly the more anterior granular and dysgranular areas.12,13,14 Yet, how these anatomical differences influence the projection patterns of single BLA neurons to frontal cortex across rodents and primates is unknown. Using a barcoded connectomic approach, we assessed the single BLA neuron connections to frontal cortex in mice and macaques. We found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens were similarly organized in mice and macaques, BLA-FC connections differed substantially. Notably, BLA connections to subcallosal anterior cingulate cortex (scACC) in macaques were least likely to branch to other medial frontal cortex areas compared to perigenual ACC (pgACC). This pattern of connections was reversed in the mouse homologues of these areas, infralimbic and prelimbic cortex (IL and PL), mirroring functional differences between rodents and non-human primates. Taken together, these results indicate that BLA connections to FC are not linearly scaled from mice to macaques and instead the organization of single-neuron BLA connections is distinct between these species.

Beta-Band power modulation in the human amygdala differentiates between go/no-go responses in an arm reaching task.

Introduction Traditionally known for its involvement in emotional processing, the amygdala's involvement in motor control remains relatively unexplored, with sparse investigation into the neural mechanisms governing amygdaloid motor movement and inhibition. Objective This study aimed to characterize the amygdaloid beta-band (13-30 Hz) power between "Go" and "No-go" trials of an arm reaching task. Methods Ten participants with drug-resistant epilepsy implanted with stereoelectroencephalographic (SEEG) electrodes in the amygdala were enrolled in this study. SEEG data was recorded throughout discrete phases of a Direct Reach Go/No-go task, during which participants reached a touchscreen monitor or withheld movement based on a colored cue. Multitaper power analysis along with Wilcoxon signed-rank and Yates-corrected Z tests were used to assess significant modulations of beta power between the Response and Fixation (baseline) phases in the "Go" and "No-go" conditions. Results In the "Go" condition, nine out of the ten participants showed a significant decrease in relative beta-band power during the Response phase (p ≤ 0.0499). In the "No-go" condition, eight out of the ten participants presented a statistically significant increase in relative beta-band power during the Response phase (p ≤ 0.0494). Four out of the eight participants with electrodes in the contralateral hemisphere and seven out of the eight participants with electrodes in the ipsilateral hemisphere presented significant modulation in beta-band power in both the "Go" and "No-go" conditions. At the group level, no significant differences were found between the contralateral and ipsilateral sides or between genders. Conclusion This study reports beta-band power modulation in the human amygdala during voluntary movement in the setting of motor execution and inhibition. This finding supplements prior research in various brain regions associating beta-band power with motor control. The distinct beta-power modulation observed between these response conditions suggests involvement of amygdaloid oscillations in differentiating between motor inhibition and execution.

Coping with the experience of frustration throughout life: Sex- and age-specific effects of early life stress on the susceptibility to reward devaluation.

Early life stress may lead to lifelong impairments in psychophysiological functions, including emotional and reward systems. Unpredicted decrease in reward magnitude generates a negative emotional state (frustration) that may be involved with susceptibility to psychiatric disorders. We evaluated in adolescents and adult rats of both sexes whether maternal separation (MS) alters the ability to cope with an unexpected reduction of reward later in life. Litters of Wistar rats were divided into controls (non handled - NH) or subjected to MS. Animals were trained to find sugary cereal pellets; later the amount was reduced. Increased latency to reach the reward-associated area indicates higher inability to regulate frustration. The dorsal hippocampus (dHC) and basolateral amygdala (BLA) were evaluated for protein levels of NMDA receptor subunits (GluN2A/GluN2B), synaptophysin, PSD95, SNAP-25 and CRF1. We found that adult MS males had greater vulnerability to reward reduction, together with decreased GluN2A and increased GluN2B immunocontent in the dHC. MS females and adolescents did not differ from controls. We concluded that MS enhances the response to frustration in males. The change in the ratio of GluN2A and GluN2B subunits in dHC could be related to a stronger, more difficult to update, memory of the aversive experience.

Effects of chronic light cycle disruption during adolescence on circadian clock, neuronal activity rhythms, and behavior in mice.

The advent of artificial lighting, particularly during the evening and night, has significantly altered the predictable daily light and dark cycles in recent times. Altered light environments disrupt the biological clock and negatively impact mood and cognition. Although adolescents commonly experience chronic changes in light/dark cycles, our understanding of how the adolescents' brain adapts to altered light environments remains limited. Here, we investigated the impact of chronic light cycle disruption (LCD) during adolescence, exposing adolescent mice to 19 h of light and 5 h of darkness for 5 days and 12 L:12D for 2 days per week (LCD group) for 4 weeks. We showed that LCD exposure did not affect circadian locomotor activity but impaired memory and increased avoidance response in adolescent mice. Clock gene expression and neuronal activity rhythms analysis revealed that LCD disrupted local molecular clock and neuronal activity in the dentate gyrus (DG) and in the medial amygdala (MeA) but not in the circadian pacemaker (SCN). In addition, we characterized the photoresponsiveness of the MeA and showed that somatostatin neurons are affected by acute and chronic aberrant light exposure during adolescence. Our research provides new evidence highlighting the potential consequences of altered light environments during pubertal development on neuronal physiology and behaviors.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Multiple Stressors Induce Amygdalohippocampal Volume Reduction in Adult Male Rats as Detected by Longitudinal Structural Magnetic Resonance Imaging.

Background: Traumatic events can cause long-lasting and uncontrollable fear and anxiety. Posttraumatic stress disorder is an intractable mental disorder, and neurobiological mechanisms using animal models are expected to help development of posttraumatic stress disorder treatment. In this study, we combined multiple stress (MS) and longitudinal in vivo magnetic resonance imaging to reveal the effects of long-lasting anxiety-like behaviors on adult male rat brains. Methods: Twelve male Wistar rats (8 weeks old) were exposed to the MS of 1-mA footshocks and forced swimming, while 12 control rats were placed in a plastic cage. Contextual fear conditioning with 0.1-mA footshocks in a context different from the MS was conducted 15 days after the MS for both groups. Three retention tests were administered after 24 hours and 9 and 16 days. Two magnetic resonance imaging scans were conducted, one on the day before MS induction and one the day after the third retention test, with a 32-day interval. Results: The MS group showed greater freezing responses than the control group in all retention tests. Whole-brain voxel-based morphometry analyses revealed reduced gray matter volume in the anterior amygdalohippocampal area in MS group rats compared with control rats. These volume changes were negatively associated with freezing time in the third retention test in the MS group. Conclusions: These results suggest that individual variability in the amygdalohippocampal area may be related to long-lasting fear responses after severe stress.

Traumatic events can cause long-lasting and uncontrollable fear and anxiety. In this study, we combined multiple stress (MS) and longitudinal in vivo magnetic resonance imaging to reveal the effects of long-lasting anxiety-like behaviors on adult male rat brains. The MS group showed greater freezing responses than the control group in all retention tests. Brain morphometry analyses revealed reduced gray matter volume in the anterior amygdalohippocampal area in MS group rats compared with control rats. These results suggest that individual variability in the amygdalohippocampal area may be related to long-lasting fear responses after severe stress.

Cisternal, vascular, and parenchymal landmarks in amygdalohippocampectomy for mesial temporal sclerosis: an index case with learnings from 820 resections.

Cortico-amygdalo-hippocampectomy is the most common epilepsy surgery resection in adults and offers excellent outcomes. Seizure outcome benefits range from 75% to 88% with a 2%-4% adverse event rate. The safety profile and outcomes could be enhanced further by clearly defining key surgical landmarks that could also aid tumoral resections in the mesial temporal lobe and selective mesial resections. The authors present their learnings of intraoperative landmarks (cisternal, parenchymal, and vascular) and surgical substeps through an index case of cortico-amygdalo-hippocampectomy with lessons from 820 resections. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2428.

Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala.

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Subregion-specific transcriptomic profiling of rat brain reveals sex-distinct gene expression impacted by adolescent stress.

Stress during adolescence clearly impacts brain development and function. Sex differences in adolescent stress-induced or exacerbated emotional and metabolic vulnerabilities could be due to sex-distinct gene expression in hypothalamic, limbic, and prefrontal brain regions. However, adolescent stress-induced whole-genome expression changes in key subregions of these brain regions were unclear. In this study, female and male adolescent Sprague Dawley rats received one-hour restraint stress daily from postnatal day (PD) 32 to PD44. Corticosterone levels, body weights, food intake, body composition, and circulating adiposity and sex hormones were measured. On PD44, brain and blood samples were collected. Using RNA-sequencing, sex-specific differences in stress-induced differentially expressed (DE) genes were identified in subregions of the hypothalamus, limbic system, and prefrontal cortex. Canonical pathways reflected well-known sex-distinct maladies and diseases, substantiating the therapeutic potential of the DE genes found in the current study. Thus, we proposed specific sex distinct, adolescent stress-induced transcriptional changes found in the current study as examples of the molecular bases for sex differences witnessed in stress induced or exacerbated emotional and metabolic disorders. Future behavioral studies and single-cell studies are warranted to test the implications of the DE genes identified in this study in sex-distinct stress-induced susceptibilities.

Effect of kynurenic acid on enzymatic activity of the DNA base excision repair pathway in specific areas of the sheep brain.

Relatively low levels of antioxidant enzymes coupled with high oxygen metabolism result in the formation of numerous oxidative DNA damages in the tissues of the central nervous system. Recently, kynurenic acid (KYNA), knowns for its neuroprotective properties, has gained increasing attention in this context. Therefore, our hypothesis assumed that increased KYNA levels in the brain would positively influence mRNA expression of selected enzymes of the base excision repair pathway as well as enhance their efficiency in excising damaged nucleobases in specific areas of the sheep brain. The study was conducted on adult anestrous sheep (n = 18), in which two different doses of KYNA (20 and 100 µg/day) were infused into the third brain ventricle for three days. Molecular and biochemical analysis included the hypothalamus (preoptic and mediol-basal areas), hippocampus (CA3 field) and amygdala (central amygdaloid nucleus), dissected from the brain of sheep euthanized immediately after the last infusion. The results revealed a significant increase P < 0.001) in the relative mRNA abundance of N-methylpurine DNA glycosylase (MPG) following administration of both dose of KYNA across all examined tissues. The transcription of thymine-DNA glycosylase (TDG) increased significantly (P < 0.001) in all tissues in response to the lower KYNA dose compared to the control group. Moreover, 8-oxoguanine (8-oxoG) DNA glycosylase (OGG1) mRNA levels were also higher in both animal groups (P < 0.001). In addition, in the hypothalamus, hippocampus and amygdala, AP endonuclease 1 (APE1) mRNA expression increased under both doses of KYNA. Moreover, the both dose of KYNA significantly stimulated the efficiency of 8-oxoG excision in hypothalamus and amygdala (P < 0.05-0.001). The lower and higher doses of KYNA significantly influenced the effectiveness of εA and εC in all structures (P < 0.01-0.001). In conclusion, the favorable effect of KYNA in the brain may include the protection of genetic material in nerve and glial cells by stimulating the expression and efficiency of BER pathway enzymes.

Chronic stress dysregulates the Hippo/YAP/14-3-3η pathway and induces mitochondrial damage in basolateral amygdala in a mouse model of depression.

Rationale: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the Hippo/YAP/14-3-3η signaling pathway mediates mitochondrial abnormalities that result in the onset of major depressive disorder (MDD) in a mouse model. Methods: The ROC algorithm was used to identify a subpopulation of mice that were exposed to chronic unpredictable mild stress (CUMS) and exhibited the most prominent depressive phenotype (Dep). Electron microscopy, biochemical assays, quantitative PCR, and immunoblotting were used to evaluate synaptic and mitochondrial changes in the basolateral amygdala (BLA). RNA sequencing was used to explore changes in the Hippo pathway and downstream target genes. In vitro pharmacological inhibition and immunoprecipitation was used to confirm YAP/14-3-3η interaction and its role in neuronal mitochondrial dysfunction. We used virus-mediated gene overexpression and knockout in YAP transgenic mice to verify the regulatory effect of the Hippo/YAP/14-3-3η pathway on depressive-like behavior. Results: Transcriptomic data identified a large number of genes and signaling pathways that were specifically altered from the BLA of Dep mice. Dep mice showed notable synaptic impairment in BLA neurons, as well as mitochondrial damage characterized by abnormal mitochondrial morphology, compromised function, impaired biogenesis, and alterations in mitochondrial marker proteins. The Hippo signaling pathway was activated in Dep mice during CUMS, and the transcriptional regulatory activity of YAP was suppressed by phosphorylation of its Ser127 site. 14-3-3η was identified as an important co-regulatory factor of the Hippo/YAP pathway, as it can respond to chronic stress and regulate cytoplasmic retention of YAP. Importantly, the integrated Hippo/YAP/14-3-3η pathway mediated neuronal mitochondrial dysfunction and depressive behavior in Dep mice. Conclusion: The integrated Hippo/YAP/14-3-3η pathway in the BLA neuron is critical in mediating depressive-like behaviors in mice, suggesting a causal role for this pathway in susceptibility to chronic stress-induced depression. This pathway therefore may present a therapeutic target against mitochondrial dysfunction and synaptic impairment in MDD.

Wheel-Running Exercise Alleviates Anxiety-Like Behavior via Down-Regulating S-Nitrosylation of Gephyrin in the Basolateral Amygdala of Male Rats.

Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABAAR γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise.

Sensory over-responsivity and atypical neural responses to socially relevant stimuli in autism.

Although aversive responses to sensory stimuli are common in autism spectrum disorder (ASD), it remains unknown whether the social relevance of aversive sensory inputs affects their processing. We used functional magnetic resonance imaging (fMRI) to investigate neural responses to mildly aversive nonsocial and social sensory stimuli as well as how sensory over-responsivity (SOR) severity relates to these responses. Participants included 21 ASD and 25 typically-developing (TD) youth, aged 8.6-18.0 years. Results showed that TD youth exhibited significant neural discrimination of socially relevant versus irrelevant aversive sensory stimuli, particularly in the amygdala and orbitofrontal cortex (OFC), regions that are crucial for sensory and social processing. In contrast, ASD youth showed reduced neural discrimination of social versus nonsocial stimuli in the amygdala and OFC, as well as overall greater neural responses to nonsocial compared with social stimuli. Moreover, higher SOR in ASD was associated with heightened responses in sensory-motor regions to socially-relevant stimuli. These findings further our understanding of the relationship between sensory and social processing in ASD, suggesting limited attention to the social relevance compared with aversiveness level of sensory input in ASD versus TD youth, particularly in ASD youth with higher SOR.

Affective music during episodic memory recollection modulates subsequent false emotional memory traces: an fMRI study.

Music is a powerful medium that influences our emotions and memories. Neuroscience research has demonstrated music's ability to engage brain regions associated with emotion, reward, motivation, and autobiographical memory. While music's role in modulating emotions has been explored extensively, our study investigates whether music can alter the emotional content of memories. Building on the theory that memories can be updated upon retrieval, we tested whether introducing emotional music during memory recollection might introduce false emotional elements into the original memory trace. We developed a 3-day episodic memory task with separate encoding, recollection, and retrieval phases. Our primary hypothesis was that emotional music played during memory recollection would increase the likelihood of introducing novel emotional components into the original memory. Behavioral findings revealed two key outcomes: 1) participants exposed to music during memory recollection were more likely to incorporate novel emotional components congruent with the paired music valence, and 2) memories retrieved 1 day later exhibited a stronger emotional tone than the original memory, congruent with the valence of the music paired during the previous day's recollection. Furthermore, fMRI results revealed altered neural engagement during story recollection with music, including the amygdala, anterior hippocampus, and inferior parietal lobule. Enhanced connectivity between the amygdala and other brain regions, including the frontal and visual cortex, was observed during recollection with music, potentially contributing to more emotionally charged story reconstructions. These findings illuminate the interplay between music, emotion, and memory, offering insights into the consequences of infusing emotional music into memory recollection processes.

Amygdala and hippocampal substructure volumes and their association with improvement in mood symptoms in patients with mood disorders undergoing electroconvulsive therapy.

Electroconvulsive therapy (ECT) demonstrates favorable outcomes in the management of severe depressive disorders. ECT has been consistently associated with volumetric increases in the amygdala and hippocampus. However, the underlying mechanisms of these structural changes and their association to clinical improvement remains unclear. In this cross-sectional structural MRI study, we assessed the difference in amygdala subnuclei and hippocampus subfields in n = 37 patients with either unipolar or bipolar disorder immediately after eighth ECT sessions compared to (n = 40) demographically matched patients in partial remission who did not receive ECT (NoECT group). Relative to NoECT, the ECT group showed significantly larger bilateral amygdala volumes post-treatment, with the effect originating from the lateral, basal, and paralaminar nuclei and the left corticoamydaloid transition area. No significant group differences were observed for the hippocampal or cortical volumes. ECT was associated with a significant decrease in depressive symptoms. However, there were no significant correlations between amygdala subnuclei volumes and symptom improvement. Our study corroborates previous reports on increased amygdalae volumes following ECT and further identifies the subnuclei driving this effect. However, the therapeutic effect of ECT does not seem to be directly related to structural changes in the amygdala.

Scopolamine infusion in the basolateral amygdala after saccharin intake induces conditioned taste avoidance in rats.

RATIONALE: Muscarinic receptor activity in the basolateral amygdala (BLA) is known to be involved in plasticity mechanisms that underlie emotional learning. The BLA is involved in the Attenuation of Neophobia, an incidental taste learning task in which a novel taste becomes familiar and recognized as safe. OBJECTIVE: Here we assessed the role of muscarinic receptor activity in the BLA in incidental taste learning. METHODS: Young adult male Wistar rats were bilaterally implanted with cannulas aimed at BLA. After recovery, rats were randomly assigned to either vehicle or muscarinic antagonist group, for each experiment. We tested the effect of specific and non-specific muscarinic antagonists administered either 1) 20 min before novel taste presentation; 2) immediately after novel taste presentation; 3) immediately after retrieval (the second taste presentation on Day 5 -S2-) or immediately after the fifth taste presentation on Day 8 (S5). RESULTS: Non-specific muscarinic receptor antagonist scopolamine infused prior to novel taste, while not affecting novel taste preference, abolished AN, i.e., the increased preference observed in control animals on the second presentation. When administered after taste consumption, intra-BLA scopolamine not only prevented AN but caused a steep decrease in the taste preference on the second presentation. This scopolamine-induced taste avoidance was not dependent on taste novelty, nor did it generalize to another novel taste. Targeting putative postsynaptic muscarinic receptors with specific M1 or M3 antagonists appeared to produce a partial taste avoidance, while M2 antagonism had no effect. CONCLUSION: These data suggest that if a salient gustatory experience is followed by muscarinic receptors antagonism in the BLA, it will be strongly and persistently avoided in the future. The study also shows that scopolamine is not just an amnesic drug, and its cognitive effects may be highly dependent on the task and the structure involved.

Circadian Synchronization of Feeding Attenuates Rats' Food Restriction-Induced Anxiety and Amygdalar Thyrotropin-Releasing Hormone Downregulation.

Anxiety is a common comorbidity of obesity, resulting from prescribing long-term caloric restriction diets (CRDs); patients with a reduced food intake lose weight but present anxious behaviors, poor treatment adherence, and weight regain in the subsequent 5 years. Intermittent fasting (IF) restricts feeding time to 8 h during the activity phase, reducing patients' weight even with no caloric restriction; it is unknown whether an IF regime with ad libitum feeding avoids stress and anxiety development. We compared the corticosterone blood concentration between male Wistar rats fed ad libitum or calorie-restricted with all-day or IF food access after 4 weeks, along with their anxiety parameters when performing the elevated plus maze (EPM). As the amygdalar thyrotropin-releasing hormone (TRH) is believed to have anxiolytic properties, we evaluated its expression changes in association with anxiety levels. The groups formed were the following: a control which was offered food ad libitum (C-adlib) or 30% of C-adlib's energy requirements (C-CRD) all day, and IF groups provided food ad libitum (IF-adlib) or 30% of C-adlib's requirements (IF-CRD) with access from 9:00 to 17:00 h. On day 28, the rats performed the EPM and, after 30 min, were decapitated to analyze their amygdalar TRH mRNA expression by in situ hybridization and corticosterone serum levels. Interestingly, circadian feeding synchronization reduced the body weight, food intake, and animal anxiety levels in both IF groups, with ad libitum (IF-adlib) or restricted (IF-CRD) food access. The anxiety levels of the experimental groups resulted to be negatively associated with TRH expression, which supported its anxiolytic role. Therefore, the low anxiety levels induced by synchronizing feeding with the activity phase would help patients who are dieting to improve their diet therapy adherence.

Threat- and reward-related brain circuitry, perceived stress, and anxiety in adolescents during the COVID-19 pandemic: a longitudinal investigation.

The Coronavirus disease (COVID-19) pandemic led to heightened anxiety in adolescents. The basolateral amygdala (BLA) and the nucleus accumbens (NAcc) are implicated in response to stress and may contribute to anxiety. The role of threat- and reward-related circuitry in adolescent anxiety during the COVID-19 pandemic, however, is not clear. Ninety-nine adolescents underwent resting-state fMRI ∼1 year before the pandemic. Following shelter-in-place orders, adolescents reported their perceived stress and, 1 month later, their anxiety. Generalized multivariate analyses identified BLA and NAcc seed-based whole-brain functional connectivity maps with perceived stress. In the resulting significant clusters, we examined the association between seed-based connectivityand subsequent anxiety. Perceived stress was associated with bilateral BLA and NAcc connectivity across distributed clusters that included prefrontal, limbic, temporal, and cerebellar regions. Several NAcc connectivity clusters located in ventromedial prefrontal, parahippocampal, and temporal cortices were positively associated with anxiety; NAcc connectivity with the inferior frontal gyrus was negatively associated. BLA connectivity was not associated with anxiety. These results underscore the integrative role of the NAcc in responding to acute stressors and its relation to anxiety in adolescents. Elucidating the involvement of subcortical-cortical circuitry in adolescents' capacity to respond adaptively to environmental challenges can inform treatment for anxiety-related disorders.

Abnormal brain spontaneous neural activity in neuromyelitis optica spectrum disorder with neuropathic pain.

Background: Neuropathic pain is one of the most common symptoms in neuromyelitis optica spectrum disorder (NMOSD). Notwithstanding, its underlying mechanism remains obscure. Methods: The amplitude of low-frequency fluctuations (ALFF) metric was employed to investigate spontaneous neural activity alterations via resting-state functional magnetic resonance imaging (rs-MRI) data from a 3.0 T MRI scanner, in a sample of 26 patients diagnosed with NMOSD with neuropathic pain (NMOSD-WNP), 20 patients with NMOSD but without neuropathic pain (NMOSD-WoNP), and 38 healthy control (HC) subjects matched for age and sex without the comorbidity of depressive or anxious symptoms. Results: It was observed that patients with NMOSD-WNP displayed a significant ALFF decrease in the left amygdala and right anterior insula, relative to both patients with NMOSD-WoNP and HC subjects. Furthermore, ALFF values in the left amygdala were negatively correlated with the scores of the Douleur Neuropathique en 4 Questions and McGill Pain Questionnaire (both sensory and affective descriptors) in patients with NMOSD-WNP. Additionally, there were negative correlations between the ALFF values in the right anterior insula and the duration of pain and the number of relapses in patients with NMOSD-WNP. Conclusion: The present study characterizes spontaneous neural activity changes in brain regions associated with sensory and affective processing of pain and its modulation, which underscore the central aspects in patients with NMOSD-WNP. These findings might contribute to a better understanding of the pathophysiologic basis of neuropathic pain in NMOSD.

Transcriptome analysis identifies an ASD-Like phenotype in oligodendrocytes and microglia from C58/J amygdala that is dependent on sex and sociability.

BACKGROUND: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. METHODS: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. RESULTS: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. LIMITATIONS: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic. CONCLUSIONS: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.