Abbreviated Abstract: Adverse childhood experiences are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length, an established marker of cellular stress and aging, is associated with both adverse childhood experiences and psychopathology, providing the basis for an emerging literature suggesting that telomere length is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal adverse childhood experiences on both the trajectory of infant telomere length and infant social-emotional problems at 18 months of age.
Higher maternal adverse childhood experiences were associated with shorter infant telomere length across infancy and higher infant externalizing behavioral problems at 18 months. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress. These data demonstrate an interactive pathway between maternal early-life adversity and infant telomere length that predicts emerging behavioral problems in the next generations.
Esteves KC, Jones CW, Wade M, Callerame K, Smith AK, Theall KP and Drury SS: Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology. Amer. J. Psychiatry [Epub ahead of print, Sept. 6, 2019; doi: 10.1176/appi.ajp.2019.18030335].
Insulin resistance in humans is associated with increased risk of major depression. Such a relationship has been also found in rodents fed a high-fat diet. To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, Zemdegs and colleagues tested the effects of metformin, an oral antidiabetic drug, in mice fed a high fat diet. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Metformin also increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. A diet poor in branched-chain amino acids produced similar results. The authors suggest that metformin could be used as add-on therapy to conventional antidepressants to relieve depressive symptoms in patients with metabolic comorbidities.
Zemdegs J, Martin H, Pintana H, Bullich S, Manta S, et al.: Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J. Neurosci. 39(30): 5935-5948 (2019).
Abstract: “Psychiatric morbidity is high in cities, so identifying potential modifiable urban protective factors is important. We show that exposure to urban green space improves well-being in naturally behaving male and female city dwellers, particularly in districts with higher psychiatric incidence and fewer green resources. Higher green-related affective benefit was related to lower prefrontal activity during negative-emotion processing, which suggests that urban green space exposure may compensate for reduced neural regulatory capacity.”
Tost H, Reichert M, Braun U, Reinhard I, Peters R, Lautenbach S, Hoell A, Schwarz E, Ebner-Priemer U, Zipf A, Meyer-Lindenberg A: Neural correlates of individual differences in affective benefit of real-life urban green space exposure. Nature Neuroscience 22(9): 1389-1393 (2019).
Abstract: “β-amyloid (Aβ)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer’s disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Aβ-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Aβ-mediated hyperactivation. Aβ-containing AD brain extracts and purified Aβ dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Aβ-dependent neuronal dysfunction that can be active before plaque formation.”
Zott B et al.: A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 365 (6453): 559-565 (2019).
Selkoe DJ: Early network dysfunction in Alzheimer’s disease. Science 365 (6453): 540-541 (2019).
Abbreviated Abstract: “Aging drives a progressive decline in cognition and decreases synapse numbers and synaptic function in the brain, thereby increasing the risk for neurodegenerative disease. Pioneering studies showed that introduction of blood from young mice into aged mice reversed age-associated cognitive impairments and increased synaptic connectivity in brain, suggesting that young blood contains specific factors that remediate age-associated decreases in brain function. However, whether such factors in blood from young animals act directly on neurons to enhance synaptic connectivity, or whether they act by an indirect mechanism remains unknown. Moreover, which factors in young blood mediate cognitive improvements in old mice is incompletely understood. “
Here, the authors show that serum extracted from the blood of young but not old mice, directly increased dendritic arborization, augmented synapse numbers and elevated synaptic N-methyl-d-aspartate (NMDA) receptors. They suggest that thrombospondin-4 (THBS4) and SPARC-like protein 1 (SPARCL1) are mediators of this effect. Both proteins were enriched in serum from young mice. Recombinant THBS4 and SPARCL1 both increased dendritic arborization and doubled synapse numbers in cultured neurons. In addition, SPARCL1 but not THBS4 tripled NMDA receptor-mediated synaptic responses. The study concluded that at least two proteins enriched in young blood, THBS4 and SPARCL1, directly act on neurons as synaptogenic factors. These proteins may represent rejuvenation factors that enhance synaptic connectivity by increasing dendritic arborization, synapse formation, and synaptic transmission.
Gan KJ and Südhof TC: Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc. Natl. Acad. Sci USA 116(25):12524-12533 (2019).
Abstract: “Science fiction notions of altering problematic memories are starting to become reality as techniques emerge through which unique memories can be edited. Here we review memory-editing research with a focus on improving the treatment of psychopathology. Studies highlight two windows of memory vulnerability: initial storage, or consolidation; and re-storage after retrieval, or reconsolidation. Techniques have been identified that can modify memories at each stage, but translating these methods from animal models to humans has been challenging and implementation into clinical therapies has produced inconsistent benefits. The science of memory editing is more complicated and nuanced than fiction, but its rapid development holds promise for future applications.”
Phelps EA and Hofmann SG: Memory editing from science fiction to clinical practice. Nature 572(7767): 43-40 (2019).
Chen S: Optical modulation goes deep in the brain. Science 365(6452): 456-457 (2019).
“Behavioural evidence suggests that targeting just 20 neurons prompted animals to ‘see’ an image. …
Deisseroth’s team showed mice images of either horizontal or vertical bars, and trained the animals to lick from a tube of water whenever they saw the vertical bars. The scientists monitored the animals’ brains and recorded which neurons fired when the mice saw the vertical bars. They eventually identified about 20 cells per animal that seemed to be consistently associated with the vertical image.
To create the hallucinations, the researchers shone light on only these neurons — stimulating them to fire. This caused the mice to lick the tube of water as if they were seeing vertical bars, even though the animals were sitting in darkness. The mice didn’t lick the tube when the scientists stimulated the neurons linked to the image of horizontal bars.
Christof Koch, president of the Allen Institute for Brain Science in Seattle, Washington, says that the paper is a technical tour de force and an advance in optogenetics. “It’s playing the piano of the mind,” he says. …”
Reardon S: Hallucinations implanted in mouse brains using light. Nature 571: 459-460 (2019); doi: 10.1038/d41586-019-02220-4.
Abstract: “Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles. An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson’s disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1−/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease.”
Matheoud D, Cannon T, Voisin A, Penttinen A-M, et al: Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice. Nature [Epub ahead of print, July 17, 2019; doi:10.1038/s41586-019-1405-y].
Summary: Migraine is a prevalent disorder, affecting 15.1% of the world’s population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develops chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, the authors review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. They propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. Evidence from preclinical research supports this view. The implications for migraine therapy are discussed.
Edvinsson L, Haanes KA and Warfvinge K: Does inflammation have a role in migraine? Nature Reviews Neurology [Epub ahead of print, July 1, 2019: doi: 10.1038/s41582-019-0216-y.]