Mitochondria-Related Nuclear Gene Expression in the Nucleus Accumbens and Blood Mitochondrial Copy Number After Developmental Fentanyl Exposure in Adolescent Male and Female C57BL/6 Mice

The potency of the synthetic opioid fentanyl and its increased clinical availability has led to the rapid escalation of use in the general population, increased recreational exposure, and subsequently opioid-related overdoses. The wide-spread use of fentanyl has, consequently, increased the incidence of in utero exposure to the drug, but the long-term effects of this type of developmental exposure are not yet understood. Opioid use has also been linked to reduced mitochondrial copy number in blood in clinical populations, but the link between this peripheral biomarker and genetic or functional changes in reward-related brain circuitry is still unclear. Additionally, mitochondrial-related gene expression in reward-related brain regions has not been examined in the context of fentanyl exposure, despite the growing literature demonstrating drugs of abuse impact mitochondrial function, which subsequently impacts neuronal signaling. The current study uses exposure to fentanyl via dam access to fentanyl drinking water during gestation and lactation as a model for developmental drug exposure. This perinatal drug-exposure is sufficient to impact mitochondrial copy number in circulating blood leukocytes, as well as mitochondrial-related gene expression in the nucleus accumbens (NAc), a reward-related brain structure, in a sex-dependent manner in adolescent offspring. Specific NAc gene expression is correlated with both blood mitochondrial copy number and with anxiety related behaviors dependent on developmental exposure to fentanyl and sex. These data indicate that developmental fentanyl exposure impacts mitochondrial function in both the brain and body in ways that can impact neuronal signaling and may prime the brain for altered reward-related behavior in adolescence and later into adulthood.

Dynamic assembly of the calcium hemostasis modulator 1 channel gates ATP permeation

Calcium hemostasis modulator 1 (CALHM1) is a voltage- and Ca2+-gated ATP channel that plays an important role in neuronal signaling. The currently reported CALHM structures are all in an ATP-conducting state, and the gating mechanism of ATP permeation remains elusive. Here, we report three cryo-EM reconstructions of heptameric CALHM1s with ordered or flexible long C-terminal helices and octameric CALHM1 with flexible long C-terminal helices at resolutions of 3.2 Å, 2.9 Å, and 3.5 Å. Structural analysis revealed that the heptameric CALHM1s are in an ATP nonconducting state in which the pore diameter in the middle is approximately 6.6 Å. Compared with those inside the octameric CALHM1s, the N-helices inside heptameric CALHM1s are in the "down" position to avoid steric clash with neighboring TM1 helices. MD simulations show that the pore size is significantly increased for ATP permeation during the movement of the N-helix from the "down" position to the "up" position. Therefore, we proposed a mechanism in which the "piston-like" motion of the N-helix drives the dynamic assembly of the CALHM1 channel for ATP permeation.

Miro1-dependent mitochondrial dynamics in parvalbumin Interneurons

The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca²⁺-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in mitochondrial trafficking could alter network activity in the mouse brain. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization while PV+ interneuron mediated inhibition remained intact. These changes were accompanied by an increase in the ex vivo hippocampal γ-oscillation (30 – 80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.

High Fructose Corn Syrup-Moderate Fat Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling

The neurobiological mechanisms that mediate psychiatric comorbidities associated with metabolic disorders such as obesity, metabolic syndrome and diabetes remain obscure. High fructose corn syrup (HFCS) is widely used in beverages and is often included in food products with moderate or high fat content that have been linked to many serious health issues including diabetes and obesity. However, the impact of such foods on the brain has not been fully characterized. Here, we evaluated the effects of long-term consumption of a HFCS-Moderate Fat diet (HFCS-MFD) on behavior, neuronal signal transduction, gut microbiota, and serum metabolomic profile in mice to better understand how its consumption and resulting obesity and metabolic alterations relate to behavioral dysfunction. Mice fed HFCS-MFD for 16 weeks displayed enhanced anxiogenesis, increased behavioral despair, and impaired social interactions. Furthermore, the HFCS-MFD induced gut microbiota dysbiosis and lowered serum levels of serotonin and its tryptophan-based precursors. Importantly, the HFCS-MFD altered neuronal signaling in the ventral striatum including reduced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), increased expression of ΔFosB, increased Cdk5-dependent phosphorylation of DARPP-32, and reduced PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor. These findings suggest that HFCS-MFD-induced changes in the gut microbiota and neuroactive metabolites may contribute to maladaptive alterations in ventral striatal function that underlie neurobehavioral impairment. While future studies are essential to further evaluate the interplay between these factors in obesity and metabolic syndrome-associated behavioral comorbidities, these data underscore the important role of peripheral-CNS interactions in diet-induced behavioral and brain function. This study also highlights the clinical need to address neurobehavioral comorbidities associated with obesity and metabolic syndrome.

Neuronal extracellular vesicles mediate BDNF-dependent dendritogenesis and synapse maturation via microRNAs

Extracellular vesicles (EVs) have emerged as novel regulators of several biological processes, in part via the transfer of EV content such as microRNA; small non-coding RNAs that regulate protein production, between cells. However, how neuronal EVs contribute to trans-neuronal signaling is largely elusive. We examined the role of neuron-derived EVs in neuronal morphogenesis downstream signaling induced by brain-derived neurotrophic factor (BDNF). We found that EVs perpetuated BDNF induction of dendrite complexity and synapse maturation in naive hippocampal neurons, which was dependent on the activity of three microRNAs, miR-132-5p, miR-218 and miR-690. These microRNAs were up-regulated in BDNF-stimulated EVs. Moreover, supplementation with BDNF-EVs rescued the block of BDNF-induced phenotypes upon inhibition of miRNA activity. Our data therefore suggest a major role for EVs in BDNF-dependent morphogenesis, and provide new evidence for the functional transfer of microRNAs between neurons. This is not only an important step towards understanding the function of EVs in inter-neuronal signaling, but is also relevant for many disorders characterized by decreased BDNF signaling, such as major depression or cognitive impairment.

Chronic temperature stress inhibits reproduction and disrupts endocytosis via chaperone titration in Caenorhabditis elegans

Background Temperature influences biology at all levels, from altering rates of biochemical reactions to determining sustainability of entire ecosystems. Although extended exposure to elevated temperatures influences organismal phenotypes important for human health, agriculture, and ecology, the molecular mechanisms that drive these responses remain largely unexplored. Prolonged, mild temperature stress (48 h at 28 °C) has been shown to inhibit reproduction in Caenorhabditis elegans without significantly impacting motility or viability. Results Analysis of molecular responses to chronic stress using RNA-seq uncovers dramatic effects on the transcriptome that are fundamentally distinct from the well-characterized, acute heat shock response (HSR). While a large portion of the genome is differentially expressed ≥ 4-fold after 48 h at 28 °C, the only major class of oogenesis-associated genes affected is the vitellogenin gene family that encodes for yolk proteins (YPs). Whereas YP mRNAs decrease, the proteins accumulate and mislocalize in the pseudocoelomic space as early as 6 h, well before reproduction declines. A trafficking defect in a second, unrelated fluorescent reporter and a decrease in pre-synaptic neuronal signaling indicate that the YP mislocalization is caused by a generalized defect in endocytosis. Molecular chaperones are involved in both endocytosis and refolding damaged proteins. Decreasing levels of the major HSP70 chaperone, HSP-1, causes similar YP trafficking defects in the absence of stress. Conversely, increasing chaperone levels through overexpression of the transcription factor HSF-1 rescues YP trafficking and restores neuronal signaling. Conclusions These data implicate chaperone titration during chronic stress as a molecular mechanism contributing to endocytic defects that influence multiple aspects of organismal physiology. Notably, HSF-1 overexpression improves recovery of viable offspring after exposure to stress. These findings provide important molecular insights into understanding organismal responses to temperature stress as well as phenotypes associated with chronic protein misfolding.

Thyroid hormone: sex-dependent role in nervous system regulation and disease

Thyroid hormone (TH) regulates many functions including metabolism, cell differentiation, and nervous system development. Alteration of thyroid hormone level in the body can lead to nervous system-related problems linked to cognition, visual attention, visual processing, motor skills, language, and memory skills. TH has also been associated with neuropsychiatric disorders including schizophrenia, bipolar disorder, anxiety, and depression. Males and females display sex-specific differences in neuronal signaling. Steroid hormones including testosterone and estrogen are considered to be the prime regulators for programing the neuronal signaling in a male- and female-specific manner. However, other than steroid hormones, TH could also be one of the key signaling molecules to regulate different brain signaling in a male- and female-specific manner. Thyroid-related diseases and neurological diseases show sex-specific incidence; however, the molecular mechanisms behind this are not clear. Hence, it will be very beneficial to understand how TH acts in male and female brains and what are the critical genes and signaling networks. In this review, we have highlighted the role of TH in nervous system regulation and disease outcome and given special emphasis on its sex-specific role in male and female brains. A network model is also presented that provides critical information on TH-regulated genes, signaling, and disease.

Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation

Various neuromodulation approaches have been employed to alter neuronal spiking activity and thus regulate brain functions and alleviate neurological disorders. Infrared neural stimulation (INS) could be a potential approach for neuromodulation because it requires no tissue contact and possesses a high spatial resolution. However, the risk of overheating and an unclear mechanism hamper its application. Here we show that midinfrared stimulation (MIRS) with a specific wavelength exerts nonthermal, long-distance, and reversible modulatory effects on ion channel activity, neuronal signaling, and sensorimotor behavior. Patch-clamp recording from mouse neocortical pyramidal cells revealed that MIRS readily provides gain control over spiking activities, inhibiting spiking responses to weak inputs but enhancing those to strong inputs. MIRS also shortens action potential (AP) waveforms by accelerating its repolarization, through an increase in voltage-gated K+ (but not Na+) currents. Molecular dynamics simulations further revealed that MIRS-induced resonance vibration of –C=O bonds at the K+ channel ion selectivity filter contributes to the K+ current increase. Importantly, these effects are readily reversible and independent of temperature increase. At the behavioral level in larval zebrafish, MIRS modulates startle responses by sharply increasing the slope of the sensorimotor input–output curve. Therefore, MIRS represents a promising neuromodulation approach suitable for clinical application.