Abstract: “Mental health and well-being are consistently influenced-directly or indirectly-by multiple environmental exposures. In this review, we have attempted to address some of the most common exposures of the biophysical environment, with a goal of demonstrating how those factors interact with central structures and functions of the brain and thus influence the neurobiology of depression. We emphasize biochemical mechanisms, observational evidence, and areas for future research. Finally, we include aspects of contextual environments-city living, nature, natural disasters, and climate change-and call for improved integration of environmental issues in public health science, policies, and activities. This integration is necessary for reducing the global pandemic of depression.”
Van den Bosch M and Meyer-Lindenberg A: Environmental Exposures and Depression: Biological Mechanisms and Epidemiological Evidence. Annu. Rev. Public Health 40: 239-259 (2019).
Abstract: “Memory is coded by patterns of neural activity in distinct circuits. Therefore, it should be possible to reverse engineer a memory by artificially creating these patterns of activity in the absence of a sensory experience. In olfactory conditioning, an odor conditioned stimulus (CS) is paired with an unconditioned stimulus (US; for example, a footshock), and the resulting CS–US association guides future behavior. Here we replaced the odor CS with optogenetic stimulation of a specific olfactory glomerulus and the US with optogenetic stimulation of distinct inputs into the ventral tegmental area that mediate either aversion or reward. In doing so, we created a fully artificial memory in mice. Similarly to a natural memory, this artificial memory depended on CS–US contingency during training, and the conditioned response was specific to the CS and reflected the US valence. Moreover, both real and implanted memories engaged overlapping brain circuits and depended on basolateral amygdala activity for expression.”
Vetere G, Tran LM, Moberg S, Steadman PE, Restivo L, Morrison FG, Ressler KJ, Josselyn SA and Frankland PW: Memory formation in the absence of experience, Nature Neuroscience [Epub ahead of print, April 29, 2019; doi: 10.1038/s41593-019-0389-0].
Abstract: “The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.”
Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C: Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science [Epub ahead of print, Apr. 12, 2019; 364(6436). pii: eaat8078. doi: 10.1126/science.aat8078].
Abbreviated abstract: Children learn language more easily than adults, though when and why this ability declines have been obscure for a number of reasons. Studying a very large number of subjects, the authors provide the first direct estimate of how grammar-learning ability changes with age, finding that it is preserved almost to the crux of adulthood (17.4 years old) and then declines steadily. This finding held not only for “difficult” syntactic phenomena but also for “easy” syntactic phenomena that are normally mastered early in acquisition. The results support the existence of a sharply-defined critical period for language acquisition, but the age of offset is much later than previously speculated. The large size of the dataset also provides novel insight into several other outstanding questions in language acquisition.
Hartshorne JK, Tenenbaum JB and Pinker S: A critical period for second language acquisition: Evidence from 2/3 million English speakers. Cognition 177: 263-277 (2018).
Summary: Noninvasive delivery of alternating electrical currents to temporal and prefrontal brain regions improves working memory and reverses age-related changes in brain dynamics in the elderly, report Reinhart and Nguyen in Nature Neuroscience (22):820–827(2019). They also report a similar effect in young adults with poor working memory performance. This method is a promising first step for successfully treating working memory deficits in the elderly.
Quentin R and Cohen LG: Reversing working memory decline in the elderly. Nature Neuroscience 22(5); 686-688 (2019).
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).
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].
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).
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.]
“’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.]