Summary: “Evidence suggests that chronic neuroinflammation has an important role in the pathogenesis of Alzheimer disease. However, in a new clinical trial, the tetracycline antibiotic minocycline, which has anti-inflammatory properties, failed to delay disease progression in individuals with mild Alzheimer disease.”
Gyengesi E and Münch G: In search of an anti-inflammatory drug for Alzheimer disease. Nature Rev Neurol. [Epub ahead of print, Jan 9, 2020; doi: 10.1038/s41582-019-0307-9].
“Human dendrites are special
A special developmental program in the human brain drives the disproportionate thickening of cortical layer 2/3. This suggests that the expansion of layer 2/3, along with its numerous neurons and their large dendrites, may contribute to what makes us human. Gidon et al. thus investigated the dendritic physiology of layer 2/3 pyramidal neurons in slices taken from surgically resected brain tissue in epilepsy patients. Dual somatodendritic recordings revealed previously unknown classes of action potentials in the dendrites of these neurons, which make their activity far more complex than has been previously thought. These action potentials allow single neurons to solve two long-standing computational problems in neuroscience that were considered to require multilayer neural networks.”
Gideon A, Zolnick TA, Fidzinski P etc all.: Dendritic action potentials and computation in human layer 2/3 cortical neurons. Science 367 (6473): 83-87 (2020).
Abstract: “Major depression is a complex disease and-among others, inflammation appears to play an important role in its pathophysiology. In this study, we investigated a broad range of cytokines in depressed patients. Plasma levels of interleukin (IL)-12/ IL-23p40, IL-15, IL-16, IL-17A, IL-1α, IL-7, tumor necrosis factorβ and vascular endothelial growth factor were compared in 48 patients suffering from major depression before, after one and after six weeks of antidepressive treatment in relation to therapy response. Interestingly, the level of IL-17A turned out to rise significantly in the non-responder group compared to responder during antidepressive treatment. IL-17A is a pro-inflammatory cytokine that initiates the production of other cytokines, thereby inducing and mediating immune response. It is also involved in allergic and autoimmune-related diseases. The database investigating the role of IL-17A in major depressive disorder has grown within the last few years comparing levels of this cytokine in depressed patients versus healthy subjects. However, little is known about the expression of IL-17Aduring the course of antidepressive treatment. In summary, our study provides valuable evidence that this cytokine might serve as a marker of therapy resistance to antidepressants.”
Nothdurfter C, Milenkovic VM, Sarubin N, Hilbert S, Manook A, Weigl J, Almeqbaali K, Wetzel CH, Rupprecht R, Baghai TC: The cytokine IL-17A as a marker of treatment resistance in major depressive disorder? Eur. J. Neurosci. 2019 Dec 2. doi: 10.1111/ejn.14636. [Epub ahead of print].
Abstract: “Chronic low-grade inflammation has been observed in major depression and other major psychiatric disorders and has been implicated in metabolic changes that are commonly associated with these disorders. This raises the possibility that the effects of dysfunctional metabolism may facilitate changes in neuronal structure and function which contribute to neuroprogression. Such changes may have implications for the progress from major depression to dementia in the elderly patient. The purpose of this review is to examine the contribution of inflammation and hypercortisolaemia, which are frequently associated with major depression, to neurodegeneration and how they detrimentally impact on brain energy metabolism. A key factor in these adverse events is insulin insensitivity caused by pro-inflammatory cytokines in association with desensitised glucocorticoid receptors. Identifying the possible metabolic changes initiated by inflammation opens new targets to ameliorate the adverse metabolic changes. This has resulted in the identification of dietary and drug targets which are of interest in the development of a new generation of psychotropic drugs.”
Leonard BE and Wegener G: Inflammation, insulin resistance and neuroprogression in depression. Acta Neuropsychiatr. 2019 Jun 12:1-9. doi: 10.1017/neu.2019.17. [Epub ahead of print]
Abstract: “Given the high prevalence and burden of mental disorders, fostering the understanding of protective factors is an urgent issue for translational medicine in psychiatry. The concept of resilience describes individual and environmental protective factors against the backdrop of established adversities linked to mental illness. There is convergent evidence for a crucial role of direct as well as indirect adversity impacting the developing brain, with persisting effects until adulthood. Direct adversity may include childhood maltreatment and family adversity, while indirect social adversity can include factors such as urban living or ethnic minority status. Recently, research has begun to examine protective factors which may be able to buffer against or even reverse these influences. First evidence indicates that supportive social environments as well as trait-like individual protective characteristics might impact on similar neural substrates, thus strengthening the capacity to actively cope with stress exposure in order to counteract the detrimental effects evoked by social adversity. Here, we provide an overview of the current literature investigating the neural mechanisms of resilience with a putative social background, including studies on individual traits and genetic variation linked to resilience. We argue that the regulatory perigenual anterior cingulate cortex and limbic regions, including the amygdala and the ventral striatum, play a key role as crucial convergence sites of protective factors. Further, we discuss possible prevention and early intervention approaches targeting both the individual and the social environment to reduce the risk of psychiatric disorders and foster resilience.”
Holz NE, Tost. H, Meyer-Lindenberg A: Resilience and the brain: a key role for regulatory circuits linked to social stress and support. Mol.. Psychiatry [Epub ahead of print Oct. 18, 2019; doi: 10.1038/s41380-019-0551-9.].
“This focus on neuroinflammation has been developed by Nature Reviews Neurology in collaboration with the European Academy of Neurology (EAN) to complement the 5th EAN Congress, where the overarching theme was neuroinflammation. The importance of neuroinflammation across neurology is becoming increasingly clear. Besides neuroinflammatory diseases, such as multiple sclerosis, roles for neuroinflammation have been identified in many apparently non-inflammatory neurological disorders, such as Alzheimer disease, stroke and epilepsy, and can even contribute to neuroprotection and repair. The Focus includes specially commissioned articles written by leading experts who spoke on neuroinflammation at the EAN Congress, providing an opportunity to read further on the subjects discussed at the meeting and highlighting the importance of the field across neurological subspecialties. The Focus is also accompanied by a Collection of recent articles from Nature Reviews Neurology that further emphasize the universal importance of neuroinflammation and the clinical opportunities that neuroinflammatory mechanisms present.”
Abstract: “Sensory experience during early developmental critical periods (CPs) has profound and long-lasting effects on cortical sensory processing perduring well into adulthood. Although recent evidence has shown that reducing cortical inhibition during adulthood reinstates CP plasticity, the precise cellular mechanisms are not well understood. Here, we show that chemogenetic inactivation of parvalbumin-positive (PV+) interneurons is sufficient to reinstate CP plasticity in the adult auditory cortex. Bidirectional manipulation of PV+ cell activity affected neuronal spectral and sound intensity selectivity and, in the case of PV+ interneuron inactivation, was mirrored by anatomical changes in PV and associated perineuronal net expression. These findings underscore the importance of sustained PV-mediated inhibitory neurotransmission throughout life and highlight the potential of chemogenetic approaches for harnessing cortical plasticity with the ultimate goal of aiding recovery from brain injury or disease.”
Cisneros-Franco JM, de Villers-Sidani É: Reactivation of critical period plasticity in adult auditory cortex through chemogenetic silencing of parvalbumin-positive interneurons. Proc Natl Acad Sci U S A. [Epub ahead of print, Dec 16, 2019; doi: 10.1073/pnas.1913227117]
Abstract: “Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.”
Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM: Chronic inflammation in the etiology of disease across the life span. Nature Medicine 25(12):1822-1832 (2019).
Article Introduction: “We examined Gollwitzer et al.’s study on autism and better social psychological knowledge with interest, given its large samples and open dataset. We commend the authors for raising the bar for autism research, which is typically underpowered and rarely draws on social psychology. Notably, their research follows recent investigations of autism-related strengths, and findings that certain social processes (e.g., social motivation) are unimpaired in autistic people who compensate for their social difficulties. Gollwitzer et al.’s article, together with recent research, is a move toward greater appreciation for autism and neurodiversity in society. …..”
Taylor EC, Livingston LA, Callan MJ, Shah P: Divergent contributions of autistic traits to social psychological knowledge. PNAS [Epub ahead of print, Dec. 10, 2019; pii: 201915787. doi: 10.1073/pnas.1915787116].