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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The behavioral state of an individual can dramatically alter how information is processed in its neural circuits. In this study, Albergaria et al. show that locomotion enhances the performance of a cerebellum-dependent behavior…….performance in delay eyeblink conditioning. Specifically, increased locomotor speed in mice drove earlier onset of learning and enhancement of learned responses that were dissociable from changes in arousal/sensory modality. Locomotor activity modulated delay eyeblink conditioning through increased activation of the mossy fiber pathway within the cerebellum. Taken together, the study provides evidence for behavioral state modulation in associative learning and suggests a “potential mechanism through which engaging in movement can improve an individual’s ability to learn”.

Albergaria C, Silva NT, Pritchett DL and Carey MR: Locomotor activity modulates associative learning in mouse cerebellum. Nature Neuroscience 21: 725–735 (2018).

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Is ‘friendly fire’ in the brain provoking Alzheimer’s disease?

Scientists want to combat dementia and neurodegeneration by keeping the brain’s immune system from going rogue.

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Abstract: “Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition.”


Grace AA and Gomes FV: The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention. Schizophr. Bull.[Epub ahead of print, Jan. 29, 2018; doi: 10.1093/schbul/sbx199.].

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“The effects of neurodegenerative syndromes extend beyond cognitive function to involve key physiological processes, including eating and metabolism, autonomic nervous system function, sleep, and motor function. Changes in these physiological processes are present in several conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease and the parkinsonian plus conditions. Key neural structures that mediate physiological changes across these conditions include neuroendocrine and hypothalamic pathways, reward pathways, motor systems and the autonomic nervous system.” In this review, the key changes in physiological processing in neurodegenerative syndromes are highlighted. The authors suggest that changes and similarities between disorders might provide novel insights into the human neural correlates of physiological functioning. These changes may provide biomarkers to aid in the early diagnosis of neurodegenerative diseases and treatment.

Ahmed RM, Ke YD, Vucic S, Ittner LM, Seeley W, Hodges JR, Piguet O, Halliday G, Kiernan MC Physiological changes in neurodegeneration  –  mechanistic insights and clinical utility. Nature Rev. Neurol. [Epub ahead of print, March 23, 2018; doi: 10.1038/nrneurol.2018.23].

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