Article excerpt:  “Nearly every scientist who has used mice or rats to study depression is familiar with the forced-swim test. The animal is dropped into a tank of water while researchers watch to see how long it tries to stay afloat. In theory, a depressed rodent will give up more quickly than a happy one — an assumption that has guided decades of research on antidepressants and genetic modifications intended to induce depression in lab mice.

But mental-health researchers have become increasingly sceptical in recent years about whether the forced-swim test is a good model for depression in people. It is not clear whether mice stop swimming because they are despondent or because they have learnt that a lab technician will scoop them out of the tank when they stop moving. Factors such as water temperature also seem to affect the results.

“We don’t know what depression looks like in a mouse,” says Eric Nestler, a neuroscientist at the Icahn School of Medicine at Mount Sinai in New York City.

Now, the animal-rights group People for the Ethical Treatment of Animals (PETA) is jumping into the fray. The group wants the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, to stop supporting the use of the forced-swim test and similar behavioural assessments by its employees and grant recipients. The tests “create intense fear, anxiety, terror, and depression in small animals” without providing useful data, PETA said in a letter to the agency on 12 July.

The animal-rights group also singled out NIMH director Joshua Gordon for using the forced-swim test in the early 2000s, when he was a researcher at Columbia University in New York City.

“The National Institute of Mental Health has for some time been discouraging the use of certain behavioral assays, including the forced swim and tail suspension test, as models of depression,” Gordon said in a statement to Nature. “While no single animal test can capture the full complexity of a human disorder, these tests in particular are recognized by many scientists as lacking sufficient mechanistic specificity to be of general use in clarifying the neurobiological mechanisms underlying human depression.”

But Gordon said that the tests are still “crucial” for some specific scientific questions, and that the NIMH will continue to fund such studies.

Although scientists insist that behavioural tests that cause stress in animals are necessary for developing human treatments, the PETA campaign dovetails with scientists’ growing concern about the quality of data produced by forced-swim tests, says Hanno Würbel, a behavioural biologist at the University of Bern. “The point is that scientists shouldn’t use these tests anymore,” he says. “In my opinion it’s just bad science.”

Sink or swim

Scientists developed the forced-swim test in the 1970s. One of its earliest applications was studying the efficacy of drugs known as selective serotonin reuptake inhibitors (SSRIs) — a class of antidepressants that includes Prozac (fluoxetine). Mice and rats that received SSRIs swam for longer periods than animals that did not.

The test’s popularity grew in the early 2000s, when scientists began modifying mouse genomes to mimic mutations linked to depression in people. Many of these researchers adopted the forced-swim test as a “quick and dirty” way to assess their ability to induce depression, even though it was not designed for that purpose, says Trevor Robbins, a neuroscientist at the University of Cambridge, UK.

By 2015, mental-health researchers were publishing an average of one paper a day that used the procedure, according to an analysis by researchers at Leiden University in the Netherlands1. Yet the swim test’s track record is mixed. It has accurately predicted whether different SSRIs are effective treatments for depression, but yields inconsistent results when used with other types of antidepressant.

And some aspects of the SSRI results are puzzling. Mice given the drugs show measurable changes in behaviour during swim tests beginning one day after treatment, whereas in people SSRIs often take weeks or months to reduce symptoms of depression.

Due in part to concerns about the forced-swim test’s accuracy, major drug companies such as Roche, Janssen and AbbVie have abandoned the procedure in recent years. ….”

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Davidsohn N, Pezone M, Vernet A, Graveline A, Oliver D, Slomovic S, Punthambaker S, Sun X, Liao R, Bonventre JV, and  Church GM: A single combination gene therapy treats multiple age-related diseases,

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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.

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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).

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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).

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Early-Life Environmental Factors Impacting the Development of Psychopathology

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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).

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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].

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“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).

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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].

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