The effect of propofol on effective brain networks.

OBJECTIVE: We compared the effective networks derived from Single Pulse Electrical Stimulation (SPES) in intracranial electrocorticography (ECoG) of awake epilepsy patients and while under general propofol-anesthesia to investigate the effect of propofol on these brain networks. METHODS: We included nine patients who underwent ECoG for epilepsy surgery evaluation. We performed SPES when the patient was awake (SPES-clinical) and repeated this under propofol-anesthesia during the surgery in which the ECoG grids were removed (SPES-propofol). We detected the cortico-cortical evoked potentials (CCEPs) with an automatic detector. We constructed two effective networks derived from SPES-clinical and SPES-propofol. We compared three network measures (indegree, outdegree and betweenness centrality), the N1-peak-latency and amplitude of CCEPs between the two effective networks. RESULTS: Fewer CCEPs were observed during SPES-propofol (median: 6.0, range: 0-29) compared to SPES-clinical (median: 10.0, range: 0-36). We found a significant correlation for the indegree, outdegree and betweenness centrality between SPES-clinical and SPES-propofol (respectively rs = 0.77, rs = 0.70, rs = 0.55, p < 0.001). The median N1-peak-latency increased from 22.0 ms during SPES-clinical to 26.4 ms during SPES-propofol. CONCLUSIONS: Our findings suggest that the number of effective network connections decreases, but network measures are only marginally affected. SIGNIFICANCE: The primary network topology is preserved under propofol.

Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1.

The voltage-sensitive sodium channel NaV1.1 plays a critical role in regulating excitability of GABAergic neurons and mutations in the corresponding gene are associated to Dravet syndrome and other forms of epilepsy. The activity of this channel is regulated by several protein kinases. To identify novel regulatory kinases we screened a library of activated kinases and we found that AKT1 was able to directly phosphorylate NaV1.1. In vitro kinase assays revealed that the phosphorylation site was located in the C-terminal part of the large intracellular loop connecting domains I and II of NaV1.1, a region that is known to be targeted by other kinases like PKA and PKC. Electrophysiological recordings revealed that activated AKT1 strongly reduced peak Na+ currents and displaced the inactivation curve to more negative potentials in HEK-293 cell stably expressing NaV1.1. These alterations in current amplitude and steady-state inactivation were mimicked by SC79, a specific activator of AKT1, and largely reverted by triciribine, a selective inhibitor. Neurons expressing endogenous NaV1.1 in primary cultures were identified by expressing a fluorescent protein under the NaV1.1 promoter. There, we also observed a strong decrease in the current amplitude after addition of SC79, but small effects on the inactivation parameters. Altogether, we propose a novel mechanism that might regulate the excitability of neural networks in response to AKT1, a kinase that plays a pivotal role under physiological and pathological conditions, including epileptogenesis.

Neuronal correlates underlying the role of the zinc sensing receptor (GPR39) in passive-coping behaviour.

The Zn2+ receptor GPR39 is proposed to be involved in the pathophysiology of depression. GPR39 knockout (KO) animals show depressive- and anxiety-like behaviour, and resistance to conventional monoamine-based antidepressants. However, it is unclear as to which brain regions are involved in the pro-depressive phenotype of GPR39KO mice and the resistance to monoamine-targeting antidepressant treatment. Our current study confirmed previous results, showing that mice lacking GPR39 display enhanced passive coping-like behaviour compared with their wild-type controls. Furthermore, this study shows for the first time that GPR39KO displayed aberrant challenge-induced neuronal activity in key brain regions associated with passive coping behaviour. Imipramine induced only a marginal reduction in the enhanced passive coping behaviour in GPR39KO mice, which was associated with attenuation of the hyperactive prefrontal cortex. Similarly, the aberrant activity within the amygdalar subregions was normalized following imipramine treatment in the GPR39KO mice, indicating that imipramine mediates these effects independently of GPR39 in the prefrontal cortex and amygdala. However, imipramine failed to modulate the aberrant brain activity in other brain regions, such as the anterior CA3 and the dentate gyrus, in GPR39KO mice. Normalization of aberrant activity in these areas has been shown previously to accompany successful behavioural effects of antidepressants. Taken together, our data suggest that monoamine-based antidepressants such as imipramine exert their action via GPR39-dependent and -independent pathways. Failure to modulate passive-coping related aberrant activity in important brain areas of the depression circuitry is proposed to mediate/contribute to the greatly reduced antidepressant action of monoamine-based antidepressants in GPR39KO mice.

The why behind the high: determinants of neurocognition during acute cannabis exposure.

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.

Dexmedetomidine inhibits unstable motor network in patients with primary motor area gliomas.

BACKGROUND: Sedative agents such as dexmedetomidine have been found to transiently exacerbate or unmask limb motor dysfunction in patients with eloquent area brain gliomas. The present study aims to investigate whether dexmedetomidine can inhibit motor plasticity in patients with glioma via fMRI. METHODS: 21 patients with brain glioma were prospectively recruited between September 2017 and December 2018. Patients were classified into pre-M1 (primary motor cortex) group (n=9), post-M1 group (n=6), and non-eloquent group (control group) (n=6) according to the tumor position related to M1. The hand movement task-fMRI and resting state fMRI (rs-fMRI) were performed before and after sedation using dexmedetomidine. The lateralization index (LI) of activation voxels and magnitude and the functional connectivity (FC) of motor network were compared before and after sedation and among different groups. RESULTS: Permanent postoperative motor deficit of the upper limb was found in 5 of 6 patients in the pre-M1 group, and none in other groups (P < .01). Task-fMRI showed the LI of activation volume and activation magnitude at M1 significantly increased only in the pre-M1 group after sedation (P < .05). Rs-fMRI showed 60.0% (27 of 45) FCs of motor network decreased in pre-M1 group after sedation (p[FDR] < .05); whereas there was no FC reduction in post-M1 and control groups (p[FDR] > .05). CONCLUSIONS: In patients with eloquent area gliomas, dexmedetomidine can inhibit the unstable compensative motor plasticity on both task- and rs-fMRI. fMRI may be a promising method for elucidating the effect of sedative agents on motor plasticity.

Perineuronal net abnormalities in Slc13a4+/- mice are rescued by postnatal administration of N-acetylcysteine.

Disruptions to either sulfate supply or sulfation enzymes can affect brain development and have long-lasting effects on brain function, yet our understanding of the molecular mechanisms governing this are incomplete. Perineuronal nets (PNNs) are highly sulfated, specialized extracellular matrix structures that regulate the maturation of synaptic connections and neuronal plasticity. We have previously shown that mice heterozygous for the brain sulfate transporter Slc13a4 have abnormal social interactions, memory, exploratory behaviors, stress and anxiety of postnatal origin, pointing to potential deficits in PNN biology, and implicate SLC13A4 as a critical factor required for regulating normal synaptic connectivity and function. Here, we sought to investigate aberrant PNN formation as a potential mechanism contributing to the functional deficits displayed by Slc13a4+/- mice. Following social interactions, we reveal reduced neuronal activation in the somatosensory cortex of Slc13a4+/- mice, and altered inhibitory and excitatory postsynaptic currents. In line with this, we found a reduction in parvalbumin-expressing neurons decorated with PNNs, as well as reduced expression of markers for PNN maturation. Finally, we reveal that postnatal administration of N-acetylcysteine prevented PNN abnormalities from manifesting in Slc13a4+/- adult animals. Collectively, these data highlight a central role for postnatal SLC13A4 in normal PNN formation, circuit function and subsequent animal behavior.

Empathy deficits and their behavioral, neuroanatomical, and functional connectivity correlates in smoked cocaine users.

Reduced empathic abilities are frequently observed in drug abusers. These deficits may compromise interpersonal interactions and contribute to diminished social functioning. However, previous evidence regarding empathy and addiction is behaviorally unspecific and virtually null in terms of their brain structural or functional correlates. Moreover, no previous study has investigated how empathy is affected by drugs whose consumption is particularly characterized by counter-empathic behaviors. Here, we conducted the first assessment of neurocognitive correlates of empathy for pain in dependent users (predominantly men) of smoked cocaine (SC, coca paste, n = 37). We compared their performance in the empathy task with that of two groups matched in relevant demographic variables: 24 dependent users of insufflated cocaine hydrochloride (CC) and 21 healthy controls. In addition, we explored the structural anatomy and functional connectivity (FC) correlates of empathic impairments across groups. Our results showed that, compared to CC and controls, SC users exhibited a selective reduction of empathic concern for intentional harms. These impairments were associated with lower gray matter volumes in regions subserving social cognition (i.e., right inferior parietal lobule, supramarginal and angular gyri). Furthermore, reduced empathic concern correlated with FC within affective empathy and social cognition networks, which are also linked to cognitive changes reported in addiction (i.e., inferior frontal and orbital gyri, posterior insula, supplementary motor area, cingulate cortex). Our findings suggest that chronic consumption of SC may involve reduced empathic concern and relevant neuroanatomical and FC abnormalities, which, in turn, may result in social interaction dysfunction. These results can inform theoretical and applied developments in neuropsychopharmacology.

Epilepsy enhance global efficiency of language networks in right temporal lobe gliomas.

AIMS: We analyzed the resting state functional magnetic resonance images to investigate the alterations of neural networks in patients with glioma-related epilepsy (GRE). METHODS: Fifty-six patients with right temporal lower-grade glioma were divided into GRE (n = 28) and non-GRE groups. Twenty-eight healthy subjects were recruited after matching age, sex, and education level. Sensorimotor, visual, language, and left executive control networks were applied to generate functional connectivity matrices, and their topological properties were investigated. RESULTS: No significant alterations in functional connectivity were found. The least significant discovery test revealed differences only in the language network. The shortest path length, clustering coefficient, local efficiency, and vulnerability were greater in the non-GRE group than in the other groups. The nodal efficiencies of two nodes (mirror areas to Broca and Wernicke) were weaker in the non-GRE group than in the other groups. The node of degree centrality (Broca), nodal local efficiency (Wernicke), and nodal clustering coefficient (temporal polar) were greater in the non-GRE group than in the healthy group. CONCLUSION: Different tumor locations alter different neural networks. Temporal lobe gliomas in the right hemisphere altered the language network. Glioma itself and GRE altered the network in opposing ways in patients with right temporal glioma.

The Effects of Kisspeptin on Brain Response to Food Images and Psychometric Parameters of Appetite in Healthy Men.

CONTEXT: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans. OBJECTIVE: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men. DESIGN: A double-blinded, randomized, placebo-controlled, crossover study was conducted. PARTICIPANTS: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2). INTERVENTION: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes. MAIN OUTCOME MEASURES: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle. RESULTS: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle. CONCLUSIONS: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism.

l-Theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry.

Chronic adolescent exposure to Δ-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. l-Theanine is an amino acid analog of l-glutamate and l-glutamine derived from various plant sources, including green tea leaves. l-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exposure in male rats, we report that l-theanine pretreatment before adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect that persists into adulthood. In addition, pretreatment with l-theanine blocked THC-induced downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and subcortical DAergic dysregulation. Finally, l-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of l-theanine in the mesocorticolimbic system.SIGNIFICANCE STATEMENT With the increasing trend of cannabis legalization and consumption during adolescence, it is essential to expand knowledge on the potential effects of adolescent cannabis exposure on brain development and identify potential pharmacological strategies to minimize Δ-9-tetrahydrocannabinol (THC)-induced neuropathology. Previous evidence demonstrates that adolescent THC exposure induces long-lasting affective and cognitive abnormalities, mesocorticolimbic dysregulation, and schizophrenia-like molecular biomarkers that persist into adulthood. We demonstrate for the first time that l-theanine, an amino acid analog of l-glutamate and l-glutamine, is capable of preventing long-term THC side effects. l-Theanine prevented the development of THC-induced behavioral aberrations, blocked cortical downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways, and normalized dysregulation of both PFC and VTA DAergic activity, demonstrating powerful and functional neuroprotective effects against THC-induced developmental neuropathology.

Cyclin-dependent kinase 4/6 inhibitors require an arcuate-to-paraventricular hypothalamus melanocortin circuit to treat diet-induced obesity.

The arcuate nucleus (ARC) of the hypothalamus comprises two antagonistic neuron populations critical for energy balance, namely, the anorexigenic pro-opiomelanocortin (POMC) and the orexigenic agouti-related peptide (AgRP) neurons that act as agonists and antagonists, respectively, for neurons expressing the type IV melanocortin receptor (MC4R) (Andermann ML and Lowell BB. Neuron 95: 757-778, 2017). MC4R activation increases energy expenditure and decreases food intake during positive energy balance states to prevent diet-induced obesity (DIO). Work from our group identified aberrant neuronal cell cycle events both as a novel biomarker and druggable target in the ARC for the treatment of DIO, demonstrating pharmacological restoration of retinoblastoma protein function in the ARC using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors could treat DIO in mice by increasing lipid oxidation to selectively decrease fat mass. However, the role of CDK4/6 inhibitors on food intake was not examined. Four-week-old Mc4r-loxTB mice were continuously administered high-fat diet (60% kcal fat). At 8 wk of age, animals were administered 60 mg/kg abemaciclib orally or a saline control and monitored every 2 wk for fat mass changes by MRI. At 11 wk of age, all animals were injected bilaterally in the paraventricular hypothalamus with AAV8 serotype virus expressing a Cre-mCherry and monitored for another 5 wk. Restoration of Mc4r expression in the paraventricular hypothalamic nucleus (PVN/PVH) reduced food intake in hyperphagic obese mice when given CDK4/6 inhibitor therapy. The reduced food intake was responsible for reduced fat mass in mice treated with abemaciclib. These results indicate that targeting POMC neurons could be an effective strategy in treating diet-related obesity.NEW & NOTEWORTHY We have defined some of the necessary components to prevent high-fat diet-induced obesity at the molecular and cellular level. Within POMC neurons, the retinoblastoma protein must remain active and prevented from phosphoinactivation by cyclin-dependent kinases. The downstream neurons within the PVH must also properly express MC4R for the circuit to appropriately regulate feeding behavior.

Progress in modelling of brain dynamics during anaesthesia and the role of sleep-wake circuitry.

General anaesthesia is used widely in surgery and during interventional medical procedures, but little is known about the exact neural mechanisms for how unconsciousness arises from administering an anaesthetic drug. Computational modelling of brain dynamics has already provided valuable insights into the neural circuitry involved in generating this state. Current theories for the origin of electroencephalographic (EEG) features in brain activity under GABAergic anaesthetic drugs have been proposed through modelling results. While much attention has been paid to describing alpha and delta oscillations, burst suppression, paradoxical excitation and the possibility of hysteresis during transitions to and from unconscious state, these models have focused only on the role of the thalamocortical system. Recent empirical findings suggest that anaesthetic drugs may act directly on the neural circuitry regulating sleep and wake states and circadian rhythms in the hypothalamus. Coupled with the common behavioural features found in physiological sleep and general anaesthesia, this evidence serves as a foundation for the 'shared circuits hypothesis' which proposes that anaesthetic-induced unconsciousness arises predominantly through modulation of the hypothalamic sleep-wake switch. This paper reviews the key findings from computational models describing brain states during the administration of anaesthetic drugs, with a focus on those enhancing GABAergic inhibition given their widespread use in practice and that almost all models of anaesthesia have focused on these drugs. We draw physiological and behavioural links between brain states during sleep and anaesthesia, and aim to highlight the importance of computational modelling in advancing our understanding of anaesthesia by considering sleep and circadian mechanisms in generating unconsciousness in future work.

Common Pathways for Pain and Depression-Implications for Practice.

BACKGROUND: Pain and depression have a high impact on caring for the people who need palliative care, but both of these are neglected compared with the approach for other symptoms encountered by these patients. AREAS OF UNCERTAINTY: There are few studies in humans that support the existence of common neural circuits between depression and pain that also explore the use of drugs with effects in both conditions. More knowledge is needed about the relationship of these clinical entities that will lead to the optimization of the treatment and improvement of quality of life. DATA SOURCES: We conducted a search in PubMed to identify relevant articles and reviews that have been published in the last 5 years, concerning the topic of common pathways between depression and pain (2014-April 2019). THERAPEUTIC ADVANCES: The connections between the 2 clinical entities start at the level of the cortical regions. The hippocampus is the main site of neural changes, modification of the immune system, neuromodulators, neurotransmitters, and signaling pathways implicated in both conditions. Increased levels of peripheral proinflammatory cytokines and neuroinflammatory changes are related to the physiopathology of these entities. Inflammation links depression and pain by altering neural circuits and changes in their common cortical regions. Antidepressants are used to treat depression and chronic, pain but more experimental studies are needed to determine which antidepressant drugs are the most effective in treating the 2 entities. CONCLUSIONS: Pharmacological and nonpharmacological interventions targeting cortical changes in pain and depression are promising, but more clinical studies are needed to validate their usefulness.

Chronic intermittent hypoxia transiently increases hippocampal network activity in the gamma frequency band and 4-Aminopyridine-induced hyperexcitability in vitro.

Chronic intermittent hypoxia (CIH) is the most distinct feature of obstructive sleep apnea (OSA), a common breathing and sleep disorder that leads to several neuropathological consequences, including alterations in the hippocampal network and in seizure susceptibility. However, it is currently unknown whether these alterations are permanent or remit upon normal oxygenation. Here, we investigated the effects of CIH on hippocampal spontaneous network activity and hyperexcitability in vitro and explored whether these alterations endure or fade after normal oxygenation. Results showed that applying CIH for 21 days to adult rats increases gamma-band hippocampal network activity and aggravates 4-Aminopyridine-induced epileptiform activity in vitro. Interestingly, these CIH-induced alterations remit after 30 days of normal oxygenation. Our findings indicate that hippocampal network alterations and increased seizure susceptibility induced by CIH are not permanent and can be spontaneously reverted, suggesting that therapeutic interventions against OSA in patients with epilepsy, such as surgery or continuous positive airway pressure (CPAP), could be favorable for seizure control.

The effects of nicotine and cannabis co-use during adolescence and young adulthood on white matter cerebral blood flow estimates.

RATIONALE: Co-use of cannabis and nicotine is common among adolescents/young adults and is associated with poorer psychological and physical outcomes, compared with single substance use. Little is known about the impact of co-use on the developing brain. OBJECTIVES: Preliminary investigation of the effects of nicotine on white matter (WM) cerebral blood flow (CBF) in adolescents/young adults and its potential moderation by cannabis use. METHODS: Adolescent/young adult (16-22 years old) nicotine and tobacco product users (NTP; N = 37) and non-nicotine users (non-NTP; N = 26) underwent a neuroimaging session comprised of anatomical, optimized pseudo-continuous arterial spin labeling, and diffusion tensor imaging scans. Groups were compared on whole-brain WM CBF estimates and their relation to past-year cannabis use. Follow-up analyses assessed correlations between identified CBF clusters and corresponding fractional anisotropy (FA) values. RESULTS: Group by cannabis effects were observed in five clusters (voxel-wise alpha < 0.001, cluster-wise alpha < 0.05; ≥ 11 contiguous voxels): non-NTP exhibited positive correlations between CBF and cannabis use in all clusters, whereas no significant relationships were observed for NTP. Greater CBF extracted from one cluster (including portions of right superior longitudinal fasciculus) was associated with reduced FA for non-NTP group only. CONCLUSIONS: This is the first investigation of WM health as indexed by CBF, and its association with FA, in adolescents/young adults with nicotine and/or cannabis use. Results suggest that cannabis use by itself may be related to increased CBF in WM fiber tracts demonstrating poorer structural intergrity, yet the occurrence of even infrequent NTP use (greater than once per month) appears to diminish this relationship.

Gene coexpression patterns predict opiate-induced brain-state transitions.

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.

Synaptic effects of estrogen.

The concept that estradiol may act as a local neuromodulator in the brain, rapidly affecting connectivity and synaptic function, has been firmly established by research over the last 30 years. De novo synthesis of estradiol within the brain as well as signaling mechanisms mediating responses to the hormone have been demonstrated, along with morphological evidence indicating rapid changes in synaptic input following increases in local estradiol levels. These rapid synaptic effects may play important roles in both physiological and pathophysiological responses to changes in circulating hormone levels, as well as in neurodegenerative disease. How local effects of estradiol on synaptic plasticity are integrated into changes in the overall activity of neural networks in the brain, however, remains a subject that is only incompletely understood.

Functional reorganization of brain networks across the human menstrual cycle.

The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterone's impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterone's widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded-and perhaps driven-by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brain's functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain.

Changes in c-fos and p-CREB signaling following exposure to forced swim stress or exogenous corticosterone during morphine-induced place preference are dependent on glucocorticoid receptor in the basolateral amygdala.

Neural circuitry comprising the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HIP) are the main components of the reward circuit. Our previous behavioral data showed that forced swim stress (FSS) and corticosterone administration could inhibit the acquisition of morphine-induced conditioned place preference (CPP), and this effect was blocked by intra-basolateral amygdala (BLA) administration of RU38486, glucocorticoid receptor (GR) antagonist. Therefore, we tried to evaluate the effect of intra-BLA administration of the GR antagonist during the conditioning phase on the c-fos and p-CREB/CREB ratio expression in the AMY, NAc, PFC, and HIP of rats that underwent FSS or received exogenous corticosterone (10 mg/kg; i.p.) before morphine injection (5 mg/kg; s.c.) during 3 conditioning days. Our results showed that morphine-induced CPP could increase c-fos level and p-CREB/CREB ratio in all regions (except in the HIP). In addition, c-fos expression was elevated by FSS in all regions and blockade of GR decreased this effect. In the PFC, in addition to FSS, corticosterone could raise c-fos expression, which was blocked by RU38486. In conclusion, it seems that the intra-BLA administration of RU38486 differently modulates the effect of morphine-induced CPP on the expression of c-fos and p-CREB/CREB ratio in animals that underwent FSS or corticosterone administration.

Glibenclamide restores dopaminergic reward circuitry in obese mice through interscauplar brown adipose tissue.

BACKGROUND: Obesity, a critical feature in metabolic disorders, is associated with medical depression. Recent evidence reveals that brown adipose tissue (BAT) activity may contribute to mood disorders, Adenosine triphosphate (ATP)-sensitive K+ (KATP) channels regulate BAT sympathetic nerve activity. However, the mechanism through which BAT activity affects mood control remains unknown. We hypothesized the BAT is involved in depressive-like symptoms regulation by trafficking KATP channels. METHODS: Eight-week-old male B6 mice fed with a high-fat diet (HFD) for 12 weeks exhibited characteristics of metabolic disorders, including hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as depressive symptoms. In this study, we surgically removed interscapular BAT in mice, and these mice exhibited immobility in the forced swim test and less preference for sugar water compared with other mice. To delineate the role of KATP channels in BAT activity regulation, we implanted a miniosmotic pump containing glibenclamide (GB), a KATP channel blocker, into the interscapular BAT of HFD-fed mice. RESULTS: GB infusion improved glucose homeostasis, insulin sensitivity, and depressive-like symptoms. KATP channel expression was lower in HFD-fed mice than in chow-fed mice. Notably, GB infusion in HFD-fed mice restored KATP channel expression. CONCLUSION: KATP channels are functionally expressed in BAT, and inhibiting BAT-KATP channels improves metabolic syndromes and reduces depressive symptoms through beta-3-adrenergic receptor-mediated protein kinase A signaling.