Abstract: “The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.”

Brusini I, Carneiro M, Wang C, Rubin C-J, Ring H, Afonso S, José A et al: Changes in brain architecture are consistent with altered fear processing in domestic rabbits. Proc.Natl.Acad. Sci. USA 115 (28): 7380-7385 (2018).


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“While accounting for only 2% of the body’s weight, the brain utilizes up to 20% of the body’s total energy. Not surprisingly, metabolic dysfunction and energy supply-and-demand mismatch have been implicated in a variety of neurological and psychiatric disorders. Mitochondria are responsible for providing the brain with most of its energetic demands, and the brain uses glucose as its exclusive energy source. Exploring the role of mitochondrial dysfunction in the etiology of psychiatric disease is a promising avenue to investigate further. Genetic analysis of mitochondrial activity is a cornerstone in understanding disease pathogenesis related to metabolic dysfunction. In concert with neuroimaging and pathological study, genetics provides an important bridge between biochemical findings and clinical correlates in psychiatric disease. Mitochondrial genetics has several unique aspects to its analysis, and corresponding special considerations.” Here, the authors review the components of mitochondrial genetic analysis – nuclear DNA, mitochondrial DNA, mitochondrial pathways, pseudogenes, nuclear-mitochondrial mismatch, and microRNAs – that could contribute to an observable clinical phenotype. This paper highlights psychiatric diseases that can arise due to dysfunction in these processes, with a focus on schizophrenia and bipolar disorder.

Cuperfain A.B., Zhang Z.L., Kennedy J.L., Gonçalves V.F.: The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease. Mol. Neuropsychiatry 4(1): 52-69 (2018).


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Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat disorders for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease and Parkinson’s disease, but the mechanisms by which these agonists are neuroprotective are not known. Here Yun and colleagues show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in a mouse model of sporadic Parkinson’s disease.

NLY01 is a potent GLP1R agonist and is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, the study concluded that NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation.

Yun SP, Kam TI, Panicker N, Kim S, Oh Y, et al: Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nature Medicine 2018 Jun 11. doi: 10.1038/s41591-018-0051-5. [Epub ahead of print].


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Abstract: “Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.”

Brainstorm Consortium, Anttila V, Bulik-Sullivan B, Finucane HK et al.: Analysis of shared heritability in common disorders of the brain. Science 2018 Jun 22;360(6395). pii: eaap8757. doi: 10.1126/science.aap8757.


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Neurotransmitter switching in the adult mammalian brain occurs following photoperiod-induced stress, but the mechanism of regulation is unknown. Here, Meng and colleagues demonstrate that elevated activity of dopaminergic neurons in the paraventricular nucleus of the rodent hypothalamus is required for the loss of dopamine expression after long-day photoperiod exposure. The transmitter switch occurs exclusively in paraventricular nucleus dopaminergic neurons that coexpress vesicular glutamate transporter 2; it is also accompanied by a loss of dopamine D2 receptors on corticotrophin-releasing factor (CRF) neurons, and can lead to increased release of CRF.

The authors note that activity-dependent revision of signaling provides another dimension of flexibility to regulate normal behavior. Changes in transmitter identity are also likely to contribute to various brain disorders, provoking interest in transmitter switching as a therapeutic tool for patients.

Meng D, Li HQ, Deisseroth K, Leutgeb S, Spitzer NC: Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress. Proc. Natl. Acad. Sci. USA 115(20):5064-5071 (2018).


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The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. The authors of this study present a series of experiments supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. First, they present the case of a diabetes patient who displayed strongly reduced insulin requirements after treatment with bilateral deep brain stimulation (DBS) targeting the anterior limb of the internal capsule. Next, they show that DBS in this striatal area, which induced dopamine release, increased hepatic and peripheral insulin sensitivity in 14 nondiabetic patients with obsessive-compulsive disorder. Conversely, systemic dopamine depletion reduced peripheral insulin sensitivity in healthy subjects. Supporting these human data, they also demonstrate that optogenetic activation of dopamine D1 receptor-expressing neurons in the nucleus accumbens increased glucose tolerance and insulin sensitivity in mice. Together, these findings support the hypothesis that striatal neuronal activity regulates systemic glucose metabolism.

Ter Horst KW, Lammers NM, Trinko R, Opland DM, Figee M, Ackermans MT, Booij J, van den Munckhof P, Schuurman PR, Fliers E, Denys D, DiLeone RJ, la Fleur SE, Serlie MJ : Striatal dopamine regulates systemic glucose metabolism in humans and mice. Science Transl. Med. 10(442). pii: eaar3752. doi: 10.1126/scitranslmed.aar3752; May 23, 2018.


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Summary: “What is the physical basis of memory? What does it take to retrieve a memory in the brain? What would it take to activate or erase memories? In the early 20th century, the German zoologist Richard Semon coined the term “engram” to denote the physical manifestation of a memory in the brain. Two decades later, Canadian psychologist Donald Hebb posited a physiological correlate for learning and recollection: The process of learning strengthens the connections, or synapses, between neurons, which leads to the development of brain-wide cell assemblies that undergo changes in their structural and functional connectivity. The coordinated activity of these assemblies—called ensembles, traces, or engrams—that occurs during learning (memory formation) is thought to be reengaged during recall and thereby forms a stable neuronal correlate of memory. As subsequent memories are formed, the dynamics of these assemblies evolve and provide preexisting scaffolds to influence how the brain processes the variety of memories an organism forms. (Recent studies have developed)… new technologies to visualize discrete engrams in the brain and modulate them in a synapse-specific manner to understand memory strength and memory restoration from an amnestic state. This improved understanding could eventually be translated to modulate memories to alleviate maladaptive memory states.”

Ramirez S: Crystallizing a memory. Science 360(6394): 1182-1183 (2018); doi: 10.1126/science.aau0043


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Currently, no reliable predictors of cognitive impairment in Parkinson’s disease exist. The authors hypothesized that microstructural changes in specific cholinergic and limbic pathways underlie cognitive impairment in Parkinson’s disease. They performed cross-sectional comparisons between patients with Parkinson’s disease with and without cognitive impairment. They also performed longitudinal 36-month follow-ups of cognitively intact Parkinson’s disease patients. Parkinson’s patients with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to Parkinson’s patients without cognitive impairment. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for cognitive impairment in Parkinson’s disease. The study concluded that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might show use as a reliable biomarker in patients at risk of cognitive decline.

Schulz J, Pagano G, Fernández Bonfante JA, Wilson H, Politis M: Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson’s disease. Brain 141(5):1501-1516 (2018).


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“Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or to move? It is often presumed that motivation involves slow (‘tonic’) dopamine changes, while fast (‘phasic’) dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value and promotes movement even on subsecond timescales. Here (Berke describes) an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time.”

Berke JD: What does dopamine mean? Nature Neuroscience [Epub ahead of print, May 14, 2018; doi: 10.1038/s41593-018-0152-y].


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The authors of this report examined the prospective relationship between physical activity and incident depression and explored potential moderators. Prospective cohort studies evaluating incident depression were searched from database inception through Oct. 18, 2017, on PubMed, PsycINFO, Embase, and SPORTDiscus. Demographic and clinical data, data on physical activity and depression assessments, and odds ratios, relative risks, and hazard ratios with 95% confidence intervals were extracted. Random-effects meta-analyses were conducted, and the potential sources of heterogeneity were explored. Methodological quality was assessed using the Newcastle-Ottawa Scale.

A total of 49 unique prospective studies were followed up for 1,837,794 person-years. Compared with people with low levels of physical activity, those with high levels had lower odds of developing depression. Furthermore, physical activity had a protective effect against the emergence of depression in youths, and in elderly persons. Protective effects against depression were found across geographical regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania. No moderators were identified. The report concluded that physical activity can confer protection against the emergence of depression regardless of age and geographical region.

Schuch FB, Vancampfort D, Firth J, Rosenbaum S, Ward PB, Silva ES, Hallgren M, Ponce De Leon A, Dunn AL, Deslandes AC, Fleck MP, Carvalho AF, Stubbs B: Physical Activity and Incident Depression: A Meta-Analysis of Prospective Cohort Studies. Am J Psychiatry  [Epub ahead of print, April 25, 2018; doi: 10.1176/appi.ajp.2018.17111194.].


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