Abstract: “Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of Alzheimer’s disease. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.”
Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, Kyrargyri V, Pfeiffer T, Khennouf L, Madry C, Gong H, Richard-Loendt A, Huang W, Saito T, Saido TC, Brandner S, Sethi H, Attwell D: Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science [Epub ahead of print, June 20, 2019; pii: eaav9518. doi: 10.1126/science.aav9518 ].
Abstract: “The past decade has seen a dramatic expansion of the field of prodromal Parkinson’s disease (PD). Ten years ago, there were only six known prodromal markers of disease, none of which had more than two studies documenting diagnostic value. We now have at least 16 markers, with as many as 10 prospective studies for a single marker. This review summarizes the major advances over the last decade and speculates about the advances we will see in the decade to come. The most notable advances over the last decade came through the study of high-risk cohorts (REM sleep behavior disorder and later genetic and autonomic cohorts), the generation of more representative population-based cohorts for studying prodromal PD, major advances in neuroimaging of early disease stages, the emerging likelihood that tissue biopsy will be able to diagnose prodromal PD, and the coalescence of prodromal markers into discrete criteria. As the next decade dawns, we await increasing precision of sensitivity and specificity estimates of known markers, the discovery of new biomarkers of prodromal disease, improvements in diagnosis using combined methods/criteria (with increasing recognition of prodromal PD as one stage of the full PD spectrum), and ultimately the development of neuroprotective therapy that can be provided at the earliest stages of disease.”
Postuma, RB and Berg, D: Prodromal Parkinson’s disease: the decade past, the decade to come. Mov. Disord. 34: 665–675 (2019).
Summary: “Some of the most effective new pharmaceutical drugs are highly complex biological molecules. To make such therapies less expensive and more broadly available, drug developers seek to fashion biosimilars — good-enough copies that can be produced at large scale.” The following is a collection of articles which highlight this important new field of research…….
Abstract: “Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy.”
Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D and Friese MA: Basson Proteinopathy drives neurodegeneration in multiple sclerosis. Nature Neuroscience 22(6): 887-896 (2019).
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).