Summary: “Depression is a mental illness characterized by episodes of a sad, despondent mood and/or a loss of interest or pleasure. This pathology affects nearly 20% of the population in the United States, and treatments are limited. Indeed, in the 5 years following remission, 80% of patients will endure relapse and more than 30% of patients suffer from treatment-resistant depression. Recently, the U.S. Food and Drug Administration (FDA) approved the clinical use of esketamine nasal spray for depression that is resistant to other treatments. Esketamine is an enantiomer of ketamine, a drug with antidepressant properties, although its mechanism of action remains unclear. Brain imaging studies suggest that neuronal circuitry in the medial prefrontal cortex is involved in the physiopathology of this disorder. …..ketamine induces plasticity of dendritic spines on mPFC (medial prefrontal cortex) neurons and restores microcircuit activity and behavior in animal models of depression. This may expand therapeutic strategies for treating major depression.”

Beyeler A: Do antidepressants restore lost synapses? Science 364(6436): 129-130 (2019).

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Abstract: “A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development and for constraints that are imposed on these mechanisms as the brain matures. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/−)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury.”

Nardou R, Lewis EM, Rothhaas R, Xu R, Yang A, Boyden E, Dölen G: Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature [Epub ahead of print, Apr 3 (2019); doi: 10.1038/s41586-019-1075-9].

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Summary: “When choosing whether to act altruistically, people may compare the current option to an idiosyncratic ideal. Prosocial individuals seem to represent deviations from that ideal in the amygdala, but selfish individuals do not. Oxytocin administration makes selfish individuals look more like prosocial individuals, behaviorally and neurally….”

Roberts ID, Teoh YY, Hutcherson CA: Oxytocin and the altruistic ‘Goldilocks zone’, Nature Neurosci. 22(4): 510-512 (2019).

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Abstract: “Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.”

Huang L, Xi Y, Peng Y, Yang Y, Huang X, Fu Y, Tao Q, Xiao J, Yuan T, An K, Zhao H, Pu M, Xu F, Xue T, Luo M, So KF, Ren C: A Visual Circuit Related to Habenula Underlies the Antidepressive Effects of Light Therapy. Neuron [Epub ahead of print, Feb.9,2019; doi: 10.1016/j.neuron.2019.01.037.]

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“’Enriched environments’ are a key experimental paradigm to decipher how interactions between genes and environment change the structure and function of the brain across the lifespan of an animal. The regulation of adult hippocampal neurogenesis by environmental enrichment is a prime example of this complex interaction. As each animal in an enriched environment will have a slightly different set of experiences that results in downstream differences between individuals, enrichment can be considered not only as an external source of rich stimuli but also to provide the room for individual behaviour that shapes individual patterns of brain plasticity and thus function.”

Kempermann G: Environmental enrichment, new neurons and the neurobiology of individuality. Nature Reviews Neuroscience [Epub ahead of print, Feb. 5, 2019; doi: 10.1038/s41583-019-0120-x.]

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Abstract: “Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.”

Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, Fu T, Worringer K, Brown HE, Wang J, Kaykas A, Karmacharya R, Goold CP, Sheridan SD and Perlis RH: Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nature Neuroscience 22(3): 374-385 (2019).

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Abstract: “Sleep is integral to life. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6Chigh monocytes, develop larger atherosclerotic lesions and produce less hypocretin-a stimulatory and wake-promoting neuropeptide-in the lateral hypothalamus. Hypocretin controls myelopoiesis by restricting the production of CSF1 by hypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereas hypocretin-null and haematopoietic hypocretin-receptor-null mice develop monocytosis and accelerated atherosclerosis, sleep-fragmented mice with either haematopoietic CSF1 deficiency or hypocretin supplementation have reduced numbers of circulating monocytes and smaller atherosclerotic lesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.”

McAlpine CS, Kiss MG, Rattik S, He S, Vassalli A, Valet C, Anzai A, Chan CT, Mindur JE, Kahles F, Poller WC, Frodermann V, Fenn AM, Gregory AF, Halle L, Iwamoto Y, Hoyer FF, Binder CJ, Libby P, Tafti M, Scammell TE, Nahrendorf M, Swirski FK: Sleep modulates haematopoiesis and protects against atherosclerosis. Nature 566(7744): 383-387 (2019).

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Summary: Sigma-1 receptors subdue systemic inflammation, which can be lethal, as in the case of septic shock. Mice lacking the endoplasmic reticulum sigma-1 receptor had exacerbated responses to LPS (lipopolysaccharides) or fecal slurry. The antidepressant fluvoxamine can bind sigma-1 and acts as a receptor agonist. Therapeutic treatment of mice in two inflammatory models revealed that fluvoxamine lowered inflammatory cytokine production and improved survival. The authors suggest that repurposing fluvoxamine to enhance sigma-1 receptor activity may be beneficial for treating sepsis.

Rosen DA, Seki SM, Fernández-Castañeda A, Beiter RM, Eccles JD, Woodfolk JA, Gaultier A: Modulation of the signa-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 11, (478), Feb. 6, 2019; eaau5266; DOI: 10.1126/scitranslmed.aau5266.

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Abstract: “Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.”

Vadodaria KC, Ji Y, Skime M, Paquola A, Nelson T, Hall-Flavin D, Fredlender C, Heard KJ, Deng Y, Le AT, Dave S, Fung L, Li , Marchetto MC, Weinshilboum R, Gage FH: Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. Mol. Psychiatry [Epub ahead of print, Jan. 30, 2019; doi: 10.1038/s41380-019-0363-y].

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Summary: “UNICEF estimates that there are approximately 8 million children worldwide who live in institutions. Institutional rearing often involves severe psychosocial neglect associated with suboptimal brain and behavioral development. This study uses data from the only existing longitudinal RCT of foster care for institutionally reared children to examine trajectories of memory and executive functioning from childhood to adolescence. We show that institutional rearing is associated with persistent problems in certain functional domains, and developmental stagnancy in others, across this transitional period. There is suggestive evidence that children assigned to early foster care may demonstrate some catch-up over time. Brain activity in childhood is associated with long-term outcomes through age 16, together underscoring the impact of early neglect on children’s neurocognitive development.”

Wade M, Fox NA, Zeanah CH and Nelson III, CA: Long-term effects of institutional rearing, foster care, and brain activity on memory and executive functioning. Proc.Natl. Acad. Sci. USA 116 (5): 1808-1813 (2019).

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