Abstract: “Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, dysfunction of these neurons is involved in both degenerative and psychiatric disorders. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channel rhodopsin to readily enable cell-type specific activation. However, corresponding lines to silence these monoaminergic neurons have been lacking. We have generated two BAC transgenic mouse lines expressing the outward proton pump, enhanced ArchT3.0 (eArchT3.0), and GFP under control of the regulatory elements of either the dopamine transporter (DAT; Jax# 031663) or the tryptophan hydroxylase 2 (TPH2; Jax# 031662) gene locus. We demonstrate highly faithful and specific expression of these lines in dopaminergic and serotonergic neurons respectively. Additionally we validate effective and sensitive eArchT3.0-mediated silencing of these neurons using slice electrophysiology as well as with a well-established behavioral assay. These new transgenic tools will help expedite the study of dopaminergic and serotonergic system function in normal behavior and disease.”
Krol A, Lopez-Huerta VG, Corey TEC, Deisseroth K, Ting JT and FengG: Two eARCHT3.0 Lines for Optogenetic Silencing of Dopaminergic and Serotonergic Neurons. Frontiers Neural Circuits 2019 Feb 1;13:4. doi: 10.3389/fncir.2019.00004. eCollection 2019.
Summary: “Ketamine, an NMDA receptor antagonist, has generated intense excitement as a therapy for treatment-resistant depression. However, ketamine and its metabolites can act on a wide range of targets, including opioid receptors, which has raised concerns. Using behavioral and cellular assays in rodents, we find that blocking opioid function prevents the antidepressant-like effects of ketamine. However, in contrast to ketamine, administration of a µ-opioid agonist is hedonic and ineffective on anhedonia/avolition. Furthermore, ketamine’s cellular actions are both mimicked and occluded by an NMDAR antagonist but not by a µ-opioid agonist. These results suggest that ketamine does not act as a μ-opioid agonist, but functional μ-opioid receptors are permissive for the antidepressant effects of ketamine.
Klein ME, Chandra J, Sheriff S, Malinow R: Opiod system is necessary but not sufficient for antidepressive actions of ketamine in rodents. Proc Natl Acad Sci USA 117 (5) 2656-2662 (2020).
Summary: “The influence of migration on disease risk has long been an important consideration in multiple sclerosis (MS) epidemiological research. Taking advantage of recent methodological advances, including access to population-based administrative health data, a new study highlights the importance of country of origin and duration of residence in the host country in determining MS risk.”
Pugliatti M and Ferri C: Migration – a route to multiple sclerosis risk globalization ? Nature Reviews Neurology 16: 67-68 (2020).
Early-Life Environmental Factors Impacting the Development of Psychopathology
Abstract: “The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM+), but not of parvalbumin (PV+) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM+ interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca2+ imaging, an increased synchronous activity of mPFC SOM+ interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination.”
Scheggia D, Managò F, Maltese F, Bruni S, Nigro M, Dautan D, Latuske P, Contarini G, Gomez-Gonzalo M, Requie LM, Ferretti V, Castellani G, Mauro D, Bonavia A, Carmignoto G, Yizhar O, Papaleo F: Somatostatin interneurons in the prefrontal cortex control affective state discrimination in mice. Nature Neurosci. 23(1): 47-60 (2020).
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.].