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Brain : a Journal of Neurology Oct 2022Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the... (Review)
Review
Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.
Topics: Adult; Child; Humans; Deep Brain Stimulation; Anticonvulsants; Epilepsy; Subthalamic Nucleus; Thalamus; Epilepsies, Partial
PubMed: 35771657
DOI: 10.1093/brain/awac234 -
Progress in Neurobiology Oct 2022The human ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex is implicated in reward and emotion, but also in memory. It is shown how the human... (Review)
Review
The human ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex is implicated in reward and emotion, but also in memory. It is shown how the human orbitofrontal cortex connecting with the vmPFC and anterior cingulate cortex provide a route to the hippocampus for reward and emotional value to be incorporated into episodic memory, enabling memory of where a reward was seen. It is proposed that this value component results in primarily episodic memories with some value component to be repeatedly recalled from the hippocampus so that they are more likely to become incorporated into neocortical semantic and autobiographical memories. The same orbitofrontal and anterior cingulate regions also connect in humans to the septal and basal forebrain cholinergic nuclei, thereby helping to consolidate memory, and helping to account for why damage to the vMPFC impairs memory. The human hippocampus and vmPFC thus contribute in complementary ways to forming episodic and semantic memories.
Topics: Hippocampus; Humans; Memory, Episodic; Mental Recall; Prefrontal Cortex; Semantics
PubMed: 35870682
DOI: 10.1016/j.pneurobio.2022.102334 -
Nature Jan 2023In humans, traumatic social experiences can contribute to psychiatric disorders. It is suggested that social trauma impairs brain reward function such that social...
In humans, traumatic social experiences can contribute to psychiatric disorders. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NT) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NT neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NT neurons that occlude social reward processing.
Topics: Animals; Female; Male; Mice; Brain; Calcium; Mice, Inbred C57BL; Neural Pathways; Neurons; Neurotensin; Optogenetics; Psychological Trauma; Reward; Septal Nuclei; Social Behavior; Stress, Psychological
PubMed: 36450985
DOI: 10.1038/s41586-022-05484-5 -
The American Journal of Psychiatry Dec 2023Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors...
OBJECTIVE
Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.
METHOD
Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.
RESULTS
No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.
CONCLUSIONS
While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
Topics: Female; Humans; Animals; Mice; Depressive Disorder, Major; Genome-Wide Association Study; Depression, Postpartum; Genetic Predisposition to Disease; Bipolar Disorder; Polymorphism, Single Nucleotide
PubMed: 37849304
DOI: 10.1176/appi.ajp.20230053 -
Nature Nov 2021Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group. The dorsal CA2 (dCA2) and...
Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group. The dorsal CA2 (dCA2) and ventral CA1 (vCA1) subregions of the hippocampus, and their projection targets, have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours, but also social memory, by influencing distinct target structures.
Topics: Animals; CA2 Region, Hippocampal; Female; Glutamic Acid; Male; Memory; Mice; Neural Pathways; Neuronal Plasticity; Optogenetics; Pyramidal Cells; Receptor, Serotonin, 5-HT1B; Septal Nuclei; Serotonin; Social Behavior; Synapses
PubMed: 34616037
DOI: 10.1038/s41586-021-03956-8 -
Neuron Jun 2020Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding...
Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Feeding Behavior; GABAergic Neurons; Hyperphagia; Mice; Neural Inhibition; Neurons; Obesity; Optogenetics; Pro-Opiomelanocortin; Protein Precursors; Receptors, Opioid; Septal Nuclei; Weight Gain
PubMed: 32302532
DOI: 10.1016/j.neuron.2020.03.022 -
Nature Aug 2023Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid...
Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVH neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical 'hunger neurons' drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVH neurons.
Topics: Agouti-Related Protein; Corticotropin-Releasing Hormone; Fasting; GABAergic Neurons; gamma-Aminobutyric Acid; Hypothalamo-Hypophyseal System; Neurons; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Presynaptic Terminals; Septal Nuclei
PubMed: 37495689
DOI: 10.1038/s41586-023-06358-0 -
Science (New York, N.Y.) Feb 2023Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that the...
Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that the ejaculation experience selectively activated estrogen receptor 2 ()-expressing neurons in the bed nucleus of the stria terminalis (BNST)-BNST-and led to persistent decreases in firing threshold for days, during which time the mice displayed sexual satiety. Inhibition of hyperexcited BNST elicited fast mating recovery in satiated mice of both sexes. In males, such hyperexcitability reduced mating motivation and was partially mediated by larger HCN (hyperpolarization-activated cyclic nucleotide-gated) currents. Thus, BNST not only encode a specific mating action but also represent a persistent state of sexual satiety, and alterations in a neuronal ion channel contribute to sexual experience-dependent long-term changes to mating drive.
Topics: Animals; Female; Male; Mice; Motivation; Neurons; Satiation; Septal Nuclei; Sexual Behavior, Animal; Ejaculation; Estrogen Receptor beta
PubMed: 36758107
DOI: 10.1126/science.abl4038 -
Molecular Psychiatry Dec 2023Although clinical reports have highlighted association of the deacetylase sirtuin 1 (SIRT1) gene with anxiety, its exact role in the pathogenesis of anxiety disorders...
Although clinical reports have highlighted association of the deacetylase sirtuin 1 (SIRT1) gene with anxiety, its exact role in the pathogenesis of anxiety disorders remains unclear. The present study was designed to explore whether and how SIRT1 in the mouse bed nucleus of the stria terminalis (BNST), a key limbic hub region, regulates anxiety. In a chronic stress model to induce anxiety in male mice, we used site- and cell-type-specific in vivo and in vitro manipulations, protein analysis, electrophysiological and behavioral analysis, in vivo MiniScope calcium imaging and mass spectroscopy, to characterize possible mechanism underlying a novel anxiolytic role for SIRT1 in the BNST. Specifically, decreased SIRT1 in parallel with increased corticotropin-releasing factor (CRF) expression was found in the BNST of anxiety model mice, whereas pharmacological activation or local overexpression of SIRT1 in the BNST reversed chronic stress-induced anxiety-like behaviors, downregulated CRF upregulation, and normalized CRF neuronal hyperactivity. Mechanistically, SIRT1 enhanced glucocorticoid receptor (GR)-mediated CRF transcriptional repression through directly interacting with and deacetylating the GR co-chaperone FKBP5 to induce its dissociation from the GR, ultimately downregulating CRF. Together, this study unravels an important cellular and molecular mechanism highlighting an anxiolytic role for SIRT1 in the mouse BNST, which may open up new therapeutic avenues for treating stress-related anxiety disorders.
Topics: Animals; Male; Sirtuin 1; Corticotropin-Releasing Hormone; Mice; Anxiety; Tacrolimus Binding Proteins; Septal Nuclei; Stress, Psychological; Signal Transduction; Mice, Inbred C57BL; Disease Models, Animal; Receptors, Glucocorticoid; Neurons; Anxiety Disorders
PubMed: 37386058
DOI: 10.1038/s41380-023-02144-6