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The European Journal of Neuroscience May 2024The anterior retrosplenial cortex (aRSC) integrates multimodal sensory information into cohesive associative recognition memories. Little is known about how information...
The anterior retrosplenial cortex is required for short-term object in place recognition memory retrieval: Role of ionotropic glutamate receptors in male and female Long-Evans rats.
The anterior retrosplenial cortex (aRSC) integrates multimodal sensory information into cohesive associative recognition memories. Little is known about how information is integrated during different learning phases (i.e., encoding and retrieval). Additionally, sex differences are observed in performance of some visuospatial memory tasks; however, inconsistent findings warrant more research. We conducted three experiments using the 1-h delay object-in-place (1-h OiP) test to assess recognition memory retrieval in male and female Long-Evans rats. (i) We found both sexes performed equally in three repeated 1-h OiP test sessions. (ii) We showed infusions of a mixture of muscimol/baclofen (GABA receptor agonists) into the aRSC ~15-min prior to the test phase disrupted 1-h OiP in both sexes. (iii) We assessed the role of aRSC ionotropic glutamate receptors in 1-h OiP retrieval using another squad of cannulated rats and confirmed that infusions of either the competitive AMPA/Kainate receptor antagonist CNQX (3 mM) or competitive NMDA receptor antagonist AP-5 (30 mM) (volumes = 0.50 uL/side) significantly impaired 1-h OiP retrieval in both sexes compared to controls. Taken together, findings challenge reported sex differences and clearly establish a role for aRSC ionotropic glutamate receptors in short-term visuospatial recognition memory retrieval. Thus, modulating neural activity in the aRSC may alleviate some memory processing impairments in related disorders.
Topics: Animals; Male; Rats, Long-Evans; Female; Rats; Recognition, Psychology; Muscimol; GABA-A Receptor Agonists; Baclofen; Memory, Short-Term; Receptors, Ionotropic Glutamate; Mental Recall; Excitatory Amino Acid Antagonists; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; GABA-B Receptor Agonists
PubMed: 38411499
DOI: 10.1111/ejn.16284 -
Antioxidants (Basel, Switzerland) Feb 2024Ischemic stroke is a devastating disease leading to neurologic impairment. Compounding the issue is the very limited array of available interventions. The activation of...
Ischemic stroke is a devastating disease leading to neurologic impairment. Compounding the issue is the very limited array of available interventions. The activation of a γ-aminobutyric acid (GABA) type A receptor (GABAR) has been reported to produce neuroprotective properties during cerebral ischemia, but its mechanism of action is not yet fully understood. Here, in a rat model of photochemically induced cerebral ischemia, we found that muscimol, a GABAR agonist, modulated GABAergic signaling, ameliorated anxiety-like behaviors, and attenuated neuronal damage in rats suffering cerebral ischemia. Moreover, GABAR activation improved brain antioxidant levels, reducing the accumulation of oxidative products, which was closely associated with the NO/NOS pathway. Notably, the inhibition of autophagy markedly relieved the neuronal insult caused by cerebral ischemia. We further established an oxygen-glucose deprivation (OGD)-induced PC12 cell injury model. Both in vivo and in vitro experiments demonstrated that GABAR activation obviously suppressed autophagy by regulating the AMPK-mTOR pathway. Additionally, GABAR activation inhibited apoptosis through inhibiting the Bax/Bcl-2 pathway. These data suggest that GABAR activation exerts neuroprotective effects during cerebral ischemia through improving oxidative stress and inhibiting autophagy and apoptosis. Our findings indicate that GABAR serves as a target for treating cerebral ischemia and highlight the GABAR-mediated autophagy signaling pathway.
PubMed: 38397792
DOI: 10.3390/antiox13020194 -
Developmental Neuroscience Feb 2024Sex differences exist in the prevalence of neurodevelopmental disorders (NDDs). Part of the aetiology of NDDs has been proposed to be alterations in the balance between...
INTRODUCTION
Sex differences exist in the prevalence of neurodevelopmental disorders (NDDs). Part of the aetiology of NDDs has been proposed to be alterations in the balance between excitatory and inhibitory neurotransmission, leading to the question of whether males and females respond differently to altered neurotransmitter balance. We investigated whether pharmacological alteration of GABAA signalling in early development results in sex-dependent changes in adult behaviours associated with NDDs.
METHODS
Male and female C57BL/6J mice received intraperitoneal injections of 0.5mg/kg muscimol or saline on postnatal days (P) 3-5 and were subjected to behavioural testing, specifically open field, light dark box, marble burying, sucralose preference, social interaction and olfactory habituation/dishabituation tests between P60-90.
RESULTS
Early postnatal administration of muscimol resulted in reduced anxiety in the light dark box test in both male and female adult mice. Muscimol reduced sucralose preference in males, but not females, whereas female mice showed reduced social behaviours. Regional alterations in cortical thickness were observed in the weeks following GABAA receptor activation, pointing to an evolving structural difference in the brain underlying adult behaviour.
CONCLUSIONS
We conclude that activation of the GABAA receptor in the first week of life resulted in long-lasting changes in a range of behaviours in adulthood following altered neurodevelopment. Sex of the individual affected the nature and severity of these abnormalities, explaining part of the varied pathophysiology and neurodevelopmental diagnosis that derive from excitatory/inhibitory imbalance.
PubMed: 38325353
DOI: 10.1159/000536641 -
Proceedings of the National Academy of... Jan 2024During free viewing, faces attract gaze and induce specific fixation patterns corresponding to the facial features. This suggests that neurons encoding the facial...
During free viewing, faces attract gaze and induce specific fixation patterns corresponding to the facial features. This suggests that neurons encoding the facial features are in the causal chain that steers the eyes. However, there is no physiological evidence to support a mechanistic link between face-encoding neurons in high-level visual areas and the oculomotor system. In this study, we targeted the middle face patches of the inferior temporal (IT) cortex in two macaque monkeys using an functional magnetic resonance imaging (fMRI) localizer. We then utilized muscimol microinjection to unilaterally suppress IT neural activity inside and outside the face patches and recorded eye movements while the animals free viewing natural scenes. Inactivation of the face-selective neurons altered the pattern of eye movements on faces: The monkeys found faces in the scene but neglected the eye contralateral to the inactivation hemisphere. These findings reveal the causal contribution of the high-level visual cortex in eye movements.
Topics: Animals; Eye Movements; Neurons; Eye; Histological Techniques; Macaca
PubMed: 38198528
DOI: 10.1073/pnas.2309906121 -
Psychopharmacology May 2024The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role...
RATIONALE
The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role of the NAc core in reward and effort-based decision making is well established, its role in working memory (WM) processes is incompletely understood. The odor span task (OST) has been proposed as a measure of non-spatial working memory capacity (WMC) as it requires rodents to select a novel odor from an increasing number of familiar odors to obtain a food reward.
OBJECTIVE
To assess the role of the NAc core in the OST using (1) reversible chemical inactivation and (2) selective blockade of dopamine D1 and D2 receptors in the area.
METHODS
Well-trained male rats were tested on the OST following intra-NAc core infusions of muscimol/baclofen, the D1 receptor antagonist SCH-23390 (1 μg/hemisphere) and the D2 receptor antagonist eticlopride (1 μg/hemisphere). Behavioral measurements included the average odor span, maximum odor span, choice latency, searching vigor, and patterns of responding during foraging that may relate to impulsivity.
RESULTS
Chemical inactivation of the NAc core significantly decreased odor span relative to sham and vehicle conditions. Selective antagonism of D2, but not D1, receptors in the NAc core also produced deficits in odor span. We found that secondary behavioral measures of choice latency, searching vigor, and responding to the first odor stimulus encountered were largely unaffected by treatment.
CONCLUSIONS
These findings suggest that D2 receptors in the NAc core are required for OST performance.
Topics: Rats; Male; Animals; Receptors, Dopamine D2; Nucleus Accumbens; Odorants; Dopamine Antagonists; Dopamine; Receptors, Dopamine D1
PubMed: 38183429
DOI: 10.1007/s00213-023-06522-4 -
Neuropharmacology Mar 2024Memory reconsolidation is a process by which labile drug memories are restabilized in long-term memory stores, permitting their enduring control over drug-seeking...
Memory reconsolidation is a process by which labile drug memories are restabilized in long-term memory stores, permitting their enduring control over drug-seeking behaviors. In the present study, we investigated the involvement of the dorsal raphé nuclei (DRN) in cocaine-memory reconsolidation. Sprague-Dawley rats (male, female) were trained to self-administer cocaine in a distinct environmental context to establish contextual drug memories. They then received extinction training in a different context. Next, the rats were re-exposed to the cocaine-predictive context for 15 min to reactivate their cocaine memories or remained in their home cages (no-reactivation control). Memory reactivation was sufficient to increase c-Fos expression, an index of neuronal activation, in the DRN, but not in the median raphé nuclei, during reconsolidation, compared to no reactivation. To determine whether DRN neuronal activity was necessary for cocaine-memory reconsolidation, rats received intra-DRN baclofen plus muscimol (BM; GABA agonists) or vehicle microinfusions immediately after or 6 h after a memory reactivation session conducted with or without lever access. The effects of DRN functional inactivation on long-term memory strength, as indicated by the magnitude of context-induced cocaine seeking, were assessed 72 h later. Intra-DRN BM treatment immediately after memory reactivation with or without lever access attenuated subsequent context-induced cocaine-seeking behavior, independent of sex. Conversely, BM treatment in the adjacent periaqueductal gray (PAG) immediately after memory reactivation, or BM treatment in the DRN 6 h after memory reactivation, did not alter responding. Together, these findings indicate that the DRN plays a requisite role in maintaining cocaine-memory strength during reconsolidation.
Topics: Female; Rats; Male; Animals; Rats, Sprague-Dawley; Dorsal Raphe Nucleus; Memory; Extinction, Psychological; Cocaine
PubMed: 38176535
DOI: 10.1016/j.neuropharm.2023.109832 -
Neuropharmacology Mar 2024The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius -...
The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT receptor activation. We found an upregulation of 5-HT receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT receptor antagonist SB-699551. Moreover, application of the GABA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.
Topics: Rats; Male; Animals; Hyperalgesia; Serotonin; Rats, Sprague-Dawley; Receptors, GABA-A; Pain Measurement; Pain; Analgesics; Peripheral Nervous System Diseases; Prefrontal Cortex
PubMed: 38160874
DOI: 10.1016/j.neuropharm.2023.109830 -
Pflugers Archiv : European Journal of... Mar 2024In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges...
In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0, 3, 6, and 7 for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7 injection. Interestingly, when IVA was administered again 24 hours after the 6 IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABA receptors.
Topics: Rats; Animals; Male; Epilepsy, Absence; Rats, Wistar; Receptors, GABA-A; Calcium Channels, T-Type; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Electroencephalography; Anticonvulsants; Muscimol; Bicuculline; Calcium Channel Blockers; gamma-Aminobutyric Acid; Disease Models, Animal
PubMed: 38159130
DOI: 10.1007/s00424-023-02900-1 -
Frontiers in Pharmacology 2023Dementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids,...
Dementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids, with taurine being highly abundant in animal tissues, but declining with age in the blood. HT is a blood-brain barrier permeable drug under investigation for Alzheimer's disease. HT also has beneficial effects in a mouse model of multiple sclerosis likely through an anti-inflammatory mechanism mediated by GABA receptor (GABAR) agonism in immune cells. While both taurine and HT are structural GABA analogs and thought to be GABA mimetics at GABARs, there is uncertainty concerning their potency as GABA mimetics on native GABARs. We show that HT is a very potent GABA mimetic, as it evokes GABAR-mediated currents with an EC of 0.4 μM (vs. 3.7 μM for GABA and 116 µM for taurine) in murine cerebellar granule cells in brain slices, with both taurine and HT having similar efficacy in activating native GABARs. Furthermore, HT displaces the high affinity GABAR ligand [H]muscimol at similarly low concentrations (HT IC of 0.16 μM vs. 125 μM for taurine) in mouse brain homogenates. The potency of taurine and HT as GABAR agonists aligns with endogenous concentrations of taurine in the blood and with HT concentrations achieved in the brain following oral administration of HT or the HT pro-drug ALZ-801. Consequently, we discuss that GABARs subtypes, similar to the ones we studied here in neurons, are plausible targets for mediating the potential beneficial effects of taurine in health and life-span extension and the beneficial HT effects in dementia and autoimmune conditions.
PubMed: 38155909
DOI: 10.3389/fphar.2023.1271203 -
BioRxiv : the Preprint Server For... Nov 2023We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in...
UNLABELLED
We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults, and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggest that the cingulate cortex is engaged under difficult listening conditions, and may exert top-down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either 'Easy' or 'Hard' blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1, and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions.
SIGNIFICANCE STATEMENT
Sensory perception often occurs under challenging conditions, such a noisy background or dim environment, yet stimulus sensitivity can remain unaffected. One hypothesis is that cognitive resources are recruited to the task, thereby facilitating perceptual performance. Here, we identify a top-down cortical circuit, from cingulate to auditory cortex in the gerbils, that supports auditory perceptual performance under challenging listening conditions. This pathway is a plausible circuit that supports effortful listening, and may be degraded by hearing loss.
PubMed: 38014324
DOI: 10.1101/2023.11.10.566668