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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.
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... (Review)
Review
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; Depression; Humans; Eicosapentaenoic Acid; Antidepressive Agents; Mice
PubMed: 38945902
DOI: 10.1254/fpj.23008 -
Neurobiology of Disease Jun 2024The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel...
The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel App knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.
PubMed: 38945496
DOI: 10.1016/j.nbd.2024.106584 -
Behavioural Brain Research Jun 2024Major depressive disorder (MDD) affects millions of people worldwide, with women at a higher risk during the childbearing age. Vortioxetine (VOX) and Vilazodone (VLZ)...
Major depressive disorder (MDD) affects millions of people worldwide, with women at a higher risk during the childbearing age. Vortioxetine (VOX) and Vilazodone (VLZ) are newer antidepressants with improved therapeutic profile commonly used, but their safety during pregnancy and long-term effects on offspring are poorly understood due to paucity of literature in preclinical and clinical studies. This study aimed to investigate whether prenatal exposure to VOX and VLZ impacts depressive- and anxiety-like neurobehavioral alterations in offspring, focusing on neurotransmitter-mediated mechanisms. Pregnant Wistar dams received either VOX or VLZ, 1mg/day and 2mg/day of the drug orally from gestation day (GD) 6 to 21. The dams naturally delivered their offspring and reared until they reached postnatal day (PND) 21. Offspring of both sexes were tested for display of depressive-and anxiety-like behaviors from PND 56 to 70. After PND 70, offspring were sacrificed, and their brains were collected to estimate neurotransmitter levels. As per protocol, controls were maintained simultaneously for each experimental design. Prenatal exposure to VOX or VLZ induced an increased state of depressive- and anxiety-like behaviors in both male and female offspring. Additionally, neurotransmitter (serotonin, dopamine, and nor-epinephrine) levels in the prefrontal cortex region of the brain were substantially reduced in exposed offspring. No sex specific neurobehavioral and neurochemical implications were observed in the present study. Our findings suggest that prenatal exposure to VOX and VLZ disrupts neurochemical balance in the fetal brain, leading to long-lasting neurobehavioral impairments in offspring of both sexes.
PubMed: 38945303
DOI: 10.1016/j.bbr.2024.115128 -
European Journal of Pharmacology Jun 2024Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with...
Etanercept ameliorates chronic mild stress-induced depressive-like behavior in rats: crosstalk between MAPK and STAT3 pathways and norepinephrine and serotonin transporters.
Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with daily functioning and quality of life. Despite decades of research, the pathophysiology of depression remains incompletely understood. The correlation between depression and inflammation has recently attracted considerable attention. This study investigated the potential antidepressant effect of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, utilizing a chronic mild stress (CMS) model in rats. Male Wistar rats were divided into two groups; one following a non-stressed protocol and the other a stressed protocol for 5 weeks. From the beginning of the third week, rats were treated either with saline daily or with etanercept twice a week (0.3 mg/kg, i.p.) or with fluoxetine daily (10 mg/kg, i.p) as a reference. Etanercept exhibited comparable effects to those of fluoxetine in counteracting CMS-induced behavioral manifestation in the forced swimming and splash tests. Etanercept also restored serotonin and norepinephrine levels to control values in the prefrontal cortex (PFC). Moreover, the current study verified the antioxidant and anti-inflammatory effects of etanercept. Interestingly, etanercept halted the expression of both norepinephrine and serotonin transporters in stressed rats. This could be attributed to abrogation of the p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 3 (STAT-3) pathways in the PFC. The findings of the present study contribute to the understanding of the potential of etanercept as an antidepressant and provide insights into the neurobiological mechanisms underlying its therapeutic effects.
PubMed: 38945285
DOI: 10.1016/j.ejphar.2024.176801 -
Clinical Neurophysiology : Official... Jun 2024Transcranial magnetic stimulation (TMS) can efficiently and robustly modulate synaptic plasticity, but little is known about how TMS affects functional connectivity...
OBJECTIVE
Transcranial magnetic stimulation (TMS) can efficiently and robustly modulate synaptic plasticity, but little is known about how TMS affects functional connectivity (rs-fMRI). Accordingly, this project characterized TMS-induced rsFC changes in depressed patients who received 3 days of left prefrontal intermittent theta burst stimulation (iTBS).
METHODS
rs-fMRI was collected from 16 subjects before and after iTBS. Correlation matrices were constructed from the cleaned rs-fMRI data. Electric-field models were conducted and used to predict pre-post changes in rs-fMRI. Site by orientation heatmaps were created for vectors centered on the stimulation site and a control site (contralateral motor cortex).
RESULTS
For the stimulation site, there was a clear relationship between both site and coil orientation, and connectivity changes. As distance from the stimulation site increased, prediction accuracy decreased. Similarly, as eccentricity from the optimal orientation increased, prediction accuracy decreased. The systematic effects described above were not apparent in the heatmap centered on the control site.
CONCLUSIONS
These results suggest that rs-fMRI following iTBS changes systematically as a function of the distribution of electrical energy delivered from the TMS pulse, as represented by the e-field model.
SIGNIFICANCE
This finding lays the groundwork for future studies to individualize TMS targeting based on how predicted rs-fMRI changes might impact psychiatric symptoms.
PubMed: 38945031
DOI: 10.1016/j.clinph.2024.06.007