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Neuropsychopharmacology : Official... Jun 2024Mouse behavioral genetic mapping studies can identify genomic intervals modulating complex traits under well-controlled environmental conditions and have been used to...
Mouse behavioral genetic mapping studies can identify genomic intervals modulating complex traits under well-controlled environmental conditions and have been used to study ethanol behaviors to aid in understanding genetic risk and the neurobiology of alcohol use disorder (AUD). However, historically such studies have produced large confidence intervals, thus complicating identification of potential causal candidate genes. Diversity Outbred (DO) mice offer the ability to perform high-resolution quantitative trait loci (QTL) mapping on a very genetically diverse background, thus facilitating identification of candidate genes. Here, we studied a population of 636 male DO mice with four weeks of intermittent ethanol access via a three-bottle choice procedure, producing a progressive ethanol consumption phenotype. QTL analysis identified 3 significant (Chrs 3, 4, and 12) and 13 suggestive loci for ethanol-drinking behaviors with narrow confidence intervals (1-4 Mbp for significant QTLs). Results suggested that genetic influences on initial versus progressive ethanol consumption were localized to different genomic intervals. A defined set of positional candidate genes were prioritized using haplotype analysis, identified coding polymorphisms, prefrontal cortex transcriptomics data, human GWAS data and prior rodent gene set data for ethanol or other misused substances. These candidates included Car8, the lone gene with a significant cis-eQTL within a Chr 4 QTL for week four ethanol consumption. These results represent the highest-resolution genetic mapping of ethanol consumption behaviors in mice to date, providing identification of novel loci and candidate genes for study in relation to the neurobiology of AUD.
PubMed: 38951586
DOI: 10.1038/s41386-024-01902-6 -
Nature Communications Jun 2024While light can affect emotional and cognitive processes of the medial prefrontal cortex (mPFC), no light-encoding was hitherto identified in this region. Here,...
While light can affect emotional and cognitive processes of the medial prefrontal cortex (mPFC), no light-encoding was hitherto identified in this region. Here, extracellular recordings in awake mice revealed that over half of studied mPFC neurons showed photosensitivity, that was diminished by inhibition of intrinsically photosensitive retinal ganglion cells (ipRGCs), or of the upstream thalamic perihabenular nucleus (PHb). In 15% of mPFC photosensitive neurons, firing rate changed monotonically along light-intensity steps and gradients. These light-intensity-encoding neurons comprised four types, two enhancing and two suppressing their firing rate with increased light intensity. Similar types were identified in the PHb, where they exhibited shorter latency and increased sensitivity. Light suppressed prelimbic activity but boosted infralimbic activity, mirroring the regions' contrasting roles in fear-conditioning, drug-seeking, and anxiety. We posit that prefrontal photosensitivity represents a substrate of light-susceptible, mPFC-mediated functions, which could be ultimately studied as a therapeutical target in psychiatric and addiction disorders.
Topics: Animals; Prefrontal Cortex; Light; Mice; Retinal Ganglion Cells; Male; Neurons; Mice, Inbred C57BL; Photic Stimulation; Action Potentials
PubMed: 38951486
DOI: 10.1038/s41467-024-49794-w -
Progress in Neuro-psychopharmacology &... Jun 2024Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal...
Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal immune activation (MIA). MIA can be modelled by exposing pregnant mice to Polyinosinic: polycytidylic acid (Poly-I:C), a viral mimetic that induces an immune response and recapitulates in the offspring many neurochemical features of ASD and schizophrenia, including altered BDNF-TrkB signalling and disruptions to excitatory/inhibitory balance. Therefore, we hypothesised that a BDNF mimetic, 7,8-Dihydroxyflavone (7,8-DHF), administered prophylactically to the dam may prevent the neurobehavioural sequelae of disruptions induced by MIA. Dams were treated with 7,8-DHF in the drinking water (0.08 mg/Ml) from gestational day (GD) 9-20 and were exposed to Poly-I:C at GD17 (20 mg/kg, i.p.). Foetal brains were collected 6 h post Poly-I:C exposure for RT-qPCR analysis of BDNF, cytokine, GABAergic and glutamatergic gene targets. A second adult cohort were tested in a battery of behavioural tests relevant to schizophrenia and the prefrontal cortex and ventral hippocampus dissected for RT-qPCR analysis. Foetal brains exposed to Poly-I:C showed increased IL-6, but reduced expression of Ntrk2 and multiple GABAergic and glutamatergic markers. Anxiety-like behaviour was observed in adult offspring prenatally exposed to poly-I:C, which was accompanied by altered expression of Gria2 in the prefrontal cortex and Gria4 in the ventral hippocampus. While 7-8 DHF normalised the expression of some glutamatergic (Grm5) and GABAergic (Gabra1) genes in Poly-I:C exposed offspring, it also led to substantial alterations in offspring not exposed to Poly-I:C. Furthermore, mice exposed to 7,8-DHF prenatally showed increased pre-pulse inhibition and reduced working memory in adulthood. These data advance understanding of how 7,8-DHF and MIA prenatal exposure impacts genes critical to excitatory/inhibitory pathways and related behaviour.
PubMed: 38950841
DOI: 10.1016/j.pnpbp.2024.111078 -
NeuroImage Jun 2024Previous neuroimaging studies have reported dual-task interference (DTi) and deterioration of task performance in a cognitive-motor dual task (DT) compared to that in a...
Previous neuroimaging studies have reported dual-task interference (DTi) and deterioration of task performance in a cognitive-motor dual task (DT) compared to that in a single task (ST). Greater frontoparietal activity is a neural signature of DTi; nonetheless, the underlying mechanism of cortical network in DTi still remains unclear. This study aimed to investigate the regional brain activity and neural network changes during DTi induced by highly demanding cognitive-motor DT. Thirty-four right-handed healthy young adults performed the spiral-drawing task. They underwent a paced auditory serial addition test (PASAT) simultaneously or independently while their cortical activity was measured using functional near-infrared spectroscopy. Motor performance was determined using the balanced integration score (BIS), a balanced index of drawing speed and precision. The cognitive task of the PASAT was administered with two difficulty levels defined by 1 s (PASAT-1 s) and 2 s (PASAT-2 s) intervals, allowing for the serial addition of numbers. Cognitive performance was determined using the percentage of correct responses. These motor and cognitive performances were significantly reduced during DT, which combined a drawing and a cognitive task at either difficulty level, compared to those in the corresponding ST conditions. The DT conditions were also characterized by significantly increased activity in the right dorsolateral prefrontal cortex (DLPFC) compared to that in the ST conditions. Multivariate Granger causality (GC) analysis of cortical activity in the selected frontoparietal regions of interest further revealed selective top-down causal connectivity from the right DLPFC to the right inferior parietal cortex during DTs. Furthermore, changes in the frontoparietal GC connectivity strength between the PASAT-2 s DT and ST conditions significantly correlated negatively with changes in the percentage of correct responses. Therefore, DTi can occur even in cognitively proficient young adults, and the right DLPFC and frontoparietal network being crucial neural mechanisms underlying DTi. These findings provide new insights into DTi and its underlying neural mechanisms and have implications for the clinical utility of cognitive-motor DTs applied to clinical populations with cognitive decline, such as those with psychiatric and brain disorders.
PubMed: 38950665
DOI: 10.1016/j.neuroimage.2024.120714 -
BioRxiv : the Preprint Server For... Jun 2024Binge drinking is common among adolescents despite mounting evidence linking it to various adverse health outcomes that includes heightened pain perception. The...
Binge drinking is common among adolescents despite mounting evidence linking it to various adverse health outcomes that includes heightened pain perception. The prelimbic (PrL) cortex is vulnerable to insults from adolescent alcohol exposure and receives input from the basolateral amygdala (BLA) while sending projections to the ventrolateral periaqueductal gray (vlPAG) - two brain regions implicated in nociception. In this study, adolescent intermittent ethanol (AIE) exposure was carried out in male and female rats using a vapor inhalation procedure. Mechanical and thermal sensitivity, assessed throughout adolescence and into adulthood, revealed that AIE exposure induced protracted mechanical allodynia in both male and female rats. However, a carrageenan inflammatory paw pain challenge in adult rats revealed that AIE did not further augment carrageenan-induced hyperalgesia. To investigate synaptic function at BLA inputs onto defined populations of PrL neurons, retrobeads and viral labelling were combined with optogenetics and slice electrophysiology. Recordings from retrobead labelled cells in the PrL revealed AIE reduced BLA driven feedforward inhibition of neurons projecting from the PrL to the vlPAG (PrL neurons), resulting in augmented excitation/inhibition (E/I) balance and increased intrinsic excitability. Consistent with this finding, recordings from virally tagged PrL parvalbumin interneurons (PVINs) demonstrated that AIE exposure reduced both E/I balance at BLA inputs onto PVINs and PVIN intrinsic excitability when assessed in adulthood. These findings provide compelling evidence that AIE and acute pain alter synaptic function and intrinsic excitability within a prefrontal nociceptive circuit.
PubMed: 38948749
DOI: 10.1101/2024.06.17.599360 -
Frontiers in Neural Circuits 2024Gamma oscillations nested in a theta rhythm are observed in the hippocampus, where are assumed to play a role in sequential episodic memory, i.e., memorization and...
Gamma oscillations nested in a theta rhythm are observed in the hippocampus, where are assumed to play a role in sequential episodic memory, i.e., memorization and retrieval of events that unfold in time. In this work, we present an original neurocomputational model based on neural masses, which simulates the encoding of sequences of events in the hippocampus and subsequent retrieval by exploiting the theta-gamma code. The model is based on a three-layer structure in which individual Units oscillate with a gamma rhythm and code for individual features of an episode. The first layer (working memory in the prefrontal cortex) maintains a cue in memory until a new signal is presented. The second layer (CA3 cells) implements an auto-associative memory, exploiting excitatory and inhibitory plastic synapses to recover an entire episode from a single feature. Units in this layer are disinhibited by a theta rhythm from an external source (septum or Papez circuit). The third layer (CA1 cells) implements a hetero-associative net with the previous layer, able to recover a sequence of episodes from the first one. During an encoding phase, simulating high-acetylcholine levels, the network is trained with Hebbian (synchronizing) and anti-Hebbian (desynchronizing) rules. During retrieval (low-acetylcholine), the network can correctly recover sequences from an initial cue using gamma oscillations nested inside the theta rhythm. Moreover, in high noise, the network isolated from the environment simulates a mind-wandering condition, randomly replicating previous sequences. Interestingly, in a state simulating sleep, with increased noise and reduced synapses, the network can "dream" by creatively combining sequences, exploiting features shared by different episodes. Finally, an irrational behavior (erroneous superimposition of features in various episodes, like "delusion") occurs after pathological-like reduction in fast inhibitory synapses. The model can represent a straightforward and innovative tool to help mechanistically understand the theta-gamma code in different mental states.
Topics: Gamma Rhythm; Theta Rhythm; Humans; Models, Neurological; Imagination; Memory; Hippocampus; Neural Networks, Computer; Animals
PubMed: 38947492
DOI: 10.3389/fncir.2024.1326609 -
Frontiers in Human Neuroscience 2024Environmental sustainability is characterized by a conflict between short-term self-interest and longer-term collective interests. Self-control capacity has been...
Environmental sustainability is characterized by a conflict between short-term self-interest and longer-term collective interests. Self-control capacity has been proposed to be a crucial determinant of people's ability to overcome this conflict. Yet, causal evidence is lacking, and previous research is dominated by the use of self-report measures. Here, we modulated self-control capacity by applying inhibitory high-definition transcranial current stimulation (HD-tDCS) above the left dorsolateral prefrontal cortex (dlPFC) while participants engaged in an environmentally consequential decision-making task. The task includes conflicting and low conflicting trade-offs between short-term personal interests and long-term environmental benefits. Contrary to our preregistered expectation, inhibitory HD-tDCS above the left dlPFC, presumably by reducing self-control capacity, led to more, and not less, pro-environmental behavior in conflicting decisions. We speculate that in our exceptionally environmentally friendly sample, deviating from an environmentally sustainable default required self-control capacity, and that inhibiting the left dlPFC might have reduced participants' ability to do so.
PubMed: 38946792
DOI: 10.3389/fnhum.2024.1395426 -
Advanced Science (Weinheim,... Jul 2024Post-stroke depression is a common complication that imposes significant burdens and challenges on patients. The occurrence of depression is often associated with...
Post-stroke depression is a common complication that imposes significant burdens and challenges on patients. The occurrence of depression is often associated with frontal lobe hemorrhage, however, current understanding of the underlying mechanisms remains limited. Here, the pathogenic mechanisms associated with the circuitry connectivity, electrophysiological alterations, and molecular characteristics are investigated related to the frontal lobe in adult male mice following unilateral injection of blood in the medial prefrontal cortex (mPFC). It is demonstrated that depression is a specific neurological complication in the unilateral hematoma model of the mPFC, and the ventral tegmental area (VTA) shows a higher percentage of connectivity disruption compared to the lateral habenula (LHb) and striatum (STR). Additionally, long-range projections originating from the frontal lobe demonstrate higher damage percentages within the connections between each region and the mPFC. mPFC neurons reveal reduced neuronal excitability and altered synaptic communication. Furthermore, transcriptomic analysis identifies the involvement of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway, and targeting the JAK-STAT pathway significantly alleviates the severity of depressive symptoms. These findings improve the understanding of post-hemorrhagic depression and may guide the development of efficient treatments.
PubMed: 38946585
DOI: 10.1002/advs.202402152 -
Nihon Yakurigaku Zasshi. Folia... 2024Growing evidence has indicated that delta opioid receptor (DOP) agonists are potential psychotropic drugs such as for depression, anxiety, and PTSD. In rodent studies,...
Growing evidence has indicated that delta opioid receptor (DOP) agonists are potential psychotropic drugs such as for depression, anxiety, and PTSD. In rodent studies, we have also demonstrated that DOP agonists exhibit potent anxiolytic-like effects via the inhibition of the excitatory neuronal activity which projects to the amygdala from the prelimbic prefrontal cortex and facilitate extinction learning of contextual fear memory through PI3K-Akt signaling pathway in the infralimbic prefrontal cortex and MEK-ERK signaling pathway in the amygdala. In this article, we introduce the functional mechanisms underlying antidepressant-like effects and anti-stress effects of DOP agonists. Then, we employed a valid animal model of depression, chronic vicarious social defeat stress (cVSDS) mice, and investigated that the influence of DOP activation on pathopsychological factors in depression such as the adult hippocampal neurogenesis, hypothalamic-pituitary-adrenal (HPA) axis, and neuroinflammation. First, repeated administrations after the stress period to cVSDS mice with a selective DOP agonist, KNT-127, improved social interaction behaviors and reduced hyperactivation of the HPA axis without affecting hippocampal neurogenesis. Meanwhile, repeated KNT-127 administrations during the cVSDS period prevented the exacerbation of social interaction behaviors, dysregulation of the HPA axis, and excessive new-born neuronal cell death in the hippocampal dentate gyrus. Moreover, in both administration paradigms, KNT-127 suppressed microglial overactivation in the dentate gyrus of cVSDS mice. These results indicate that the underlying mechanism of DOP-induced antidepressant-like effects differ from those of conventional monoaminergic antidepressants. Furthermore, we propose that DOP agonists might have prophylactic effects as well as therapeutic effects on pathophysiological changes in depression.
Topics: Animals; Receptors, Opioid, delta; Psychotropic Drugs; Humans; Mice; Stress, Psychological
PubMed: 38945905
DOI: 10.1254/fpj.24011 -
Nihon Yakurigaku Zasshi. Folia... 2024Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed...
Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.
Topics: Animals; Humans; Mice; Antidepressive Agents; Depression; Eicosapentaenoic Acid
PubMed: 38945902
DOI: 10.1254/fpj.23008