Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat.

BACKGROUND: Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. METHODS: We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABA A agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. RESULTS: Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4 ±â€Š5.8 to 119.5 ±â€Š6.9 mmHg in the SHR and from 111.8 ±â€Š7.0 to 84.2 ±â€Š8.3 mmHg in the WKY and the RSNA response from 186.2 ±â€Š7.1 to 142.7 ±â€Š7.3% of baseline in the SHR and from 201.0 ±â€Š11.5 to 160.2 ±â€Š9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5 ±â€Š5.0 to 126.2 ±â€Š7.7 mmHg and the RSNA response from 189.9 ±â€Š13.7to 168.5 ±â€Š12.7% of baseline but had no effect in the WKY. CONCLUSION: These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.

Muscimol inhibits plasma membrane rupture and ninjurin-1 oligomerization during pyroptosis.

Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the pore-forming protein gasdermin D, causing plasma membrane rupture and release of pathogenic cellular contents. We previously identified muscimol as a small molecule that prevents plasma membrane rupture during pyroptosis via an unidentified mechanism. Here, we show that muscimol has reversible activity to prevent cellular lysis without affecting earlier pyroptotic events. Although muscimol is a well-characterized agonist for neuronal GABAA receptors, muscimol protection is not altered by GABAA receptor antagonists or recapitulated by other GABAA agonists, suggesting that muscimol acts via a novel mechanism. We find that muscimol blocks oligomerization of ninjurin-1, which is required for plasma membrane rupture downstream of gasdermin D pore formation. Our structure-activity relationship studies reveal distinct molecular determinants defining inhibition of pyroptotic lysis compared to GABAA binding. In addition, we demonstrate that muscimol reduces lethality during LPS-induced septic shock. Together, these findings demonstrate that ninjurin-1-mediated plasma membrane rupture can be pharmacologically modulated and pave the way toward identification of therapeutic strategies for pathologic conditions associated with pyroptosis.

Social affective behaviors among female rats involve the basolateral amygdala and insular cortex.

The ability to detect, appraise, and respond to another's emotional state is essential to social affective behavior. This is mediated by a network of brain regions responsible for integrating external cues with internal states to orchestrate situationally appropriate behavioral responses. The basolateral amygdala (BLA) and the insular cortex are reciprocally connected regions involved in social cognition and prior work in male rats revealed their contributions to social affective behavior. We investigated the functional role of these regions in female rats in a social affective preference (SAP) test in which experimental rats approach stressed juvenile but avoid stressed adult conspecifics. In separate experiments, the BLA or the insula were inhibited by local infusion of muscimol (100ng/side in 0.5µL saline) or vehicle prior to SAP tests. In both regions, muscimol interfered with preference for the stressed juvenile and naive adult, indicating that these regions are necessary for appropriate social affective behavior. In male rats, SAP behavior requires insular oxytocin but there are noteworthy sex differences in the oxytocin receptor distribution in rats. Oxytocin (500nM) administered to the insula did not alter social behavior but oxytocin infusions to the BLA increased social interaction. In sum, female rats appear to use the same BLA and insula regions for social affective behavior but sex differences exist in contribution of oxytocin in the insula.

Analysis of the Ibotenic Acid, Muscimol, and Ergosterol Content of an Amanita Muscaria Hydroalcoholic Extract with an Evaluation of Its Cytotoxic Effect against a Panel of Lung Cell Lines In Vitro.

The fungus Amanita muscaria is universally recognizable for its iconic appearance; it is also widely regarded as poisonous, inedible, and even deadly. In spite of that, there have been documented cases of use of A. muscaria-containing preparations against various diseases, including cancer, to no apparent ill effect. The search for compounds that can be used to treat cancer among various plants and fungi has been intensifying in recent years. In light of this, we describe an HPLC HILIC analytical method for the evaluation of the content of the anticancer compound ergosterol (ERG) and the neuroactive alkaloids ibotenic acid (IBO) and muscimol (MUS) that contribute significantly to the unpleasant physiological syndrome associated with A. muscaria consumption. A 'homemade' A. muscaria tincture made using 80-proof rye vodka as the solvent, an A. muscaria extract made with a standardized water-ethanol solution as the solvent, and fractions obtained from the second extract via liquid-liquid extraction with nonpolar solvents were analyzed. The study also presents the results of capillary zone electrophoresis with contactless conductivity detection and UHPLC-MS/MS analyses of the IBO and MUS content of the two native A. muscaria extracts and an evaluation of the standardized extract's cytotoxic effect against a small panel of lung cell cultures in vitro. Our results show that the standardized extract has a significant cytotoxic effect and does not contain the compounds of interest in any significant quantity.

Prelimbic cortex inactivation prevents ABA renewal based on stress state.

Our recent research suggests that the interoceptive state associated with stress can function as a contextual stimulus for operant behavior. In the present experiment, we investigated the role of the rodent prelimbic cortex (PL), a brain region that is critical in contextual control of operant behavior, in the ability of a stressed state to produce ABA renewal of an extinguished operant response. Rats were trained to perform a lever press response for a food pellet reward during daily sessions that followed exposure to a stressor that changed each day. The response was then extinguished in the absence of stress. ABA renewal of extinguished responding occurred following exposure to another stressor (different from any used during acquisition) in control rats but not in rats that received a PL-inactivating infusion (baclofen/muscimol). Results confirm that the interoceptive state of stress can play the role of a contextual stimulus and initiate renewal (relapse) of an inhibited behavior when stress has previously been associated with the behavior. In conjunction with our previous work, the present results support the hypothesis that the PL is important for contexts, both exteroceptive and interoceptive, to exert such control over operant behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties.

Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and has a very distinctive appearance with its red cap and white spotted warts. The mushroom comprises several pharmacologically active alkaloids, including muscazone, muscarine, ibotenic acid, and muscimol, the latter two compounds being potent GABA agonists. Muscimol has served as a backbone in the design of GABA agonists devoid of effects on the GABA-metabolizing enzyme, GABA transaminase, and GABA uptake systems. In this sense, several analogs of muscimol have been synthesized and studied including THIP, THPO, iso-THIP, iso-THAZ and 4-PIOL which all interact with the GABA receptors much differently. The growing pharmacological and toxicological interest based on many conflicting opinions on the use of the neuroprotective role of muscimol analogs against some neurodegenerative diseases, its potent role in the treatment of cerebral ischemia and other socially significant health conditions provided the basis for this review.

A thalamo-parietal cortex circuit is critical for place-action coordination.

The anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an individual within the environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus, ALT-PC functional connectivity would be critical for moving toward remembered allocentric locations. This hypothesis was tested in rats with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90°, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as "no selection" trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy, but only bilateral PC inactivations resulted in increased non selecting, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC circuit is critical for linking an action with a spatial location for successful navigation.

Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse.

Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively. Muscimol microinjections into the LPB significantly attenuated eVNS-evoked respiratory rate responses. Notably, muscimol injections reaching the caudal LPB, previously unrecognised for respiratory modulation, potently modulated eVNS-evoked apnoea, whilst muscimol injections reaching the intermediate LPB selectively modulated the eVNS-evoked tachypnoea. The effects of muscimol on eVNS-evoked breathing rate changes occurred without altering basal eupneic breathing. These results highlight novel roles for the LPB in regulating vagally-evoked respiratory reflexes.

Controllable Stress Increases Rapid Eye Movement Sleep in Rats: Regulation by the Central Nucleus of the Amygdala.

BACKGROUND: Training with inescapable shock (IS; uncontrollable stressor) is followed by significant decreases in rapid eye movement sleep (REM). However, controllability is important in the effects of stress. We examined the effects of escapable shock (ES; controllable stressor) on sleep and whether the central nucleus of the amygdala (CNA) plays a role in regulating these effects. METHODS: Six Wistar rats implanted with a cannula located in CNA underwent two days of ES training (20 shock presentations; 0.5 mA; 5.0 s maximum duration; 1.0 min interstimulus interval). Five days later, they were re-exposed to the shock context. RESULTS: Following shock training, REM was significantly increased in both light and dark periods. Non-REM (NREM) and total sleep (TS) duration were decreased during the light period. Similar effects on REM and NREM were observed following re-exposure to the training context alone. Microinjections of saline into CNA immediately following ES also produced similar increases in REM, whereas microinjections of muscimol (MUS; GABAA (γ-aminobutyric acid) antagonist) subsequent to ES blocked the increases in REM. CONCLUSIONS: These data, along with previous work with ES and IS, demonstrate that stressor controllability is important in determining how stress impacts sleep. Moreover, the results of the microinjection study indicate that the effects of ES on REM are regulated through the CNA.

The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice.

Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of "M2" cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.

Muscimol inactivation of dorsal striatum in young and aged male rats does not affect paired associates learning performance.

Improving cognitive health for older adults requires understanding the neurobiology of age-related cognitive decline and the mechanisms underlying preserved cognition in old age. During spatial learning tasks, aged humans and rodents shift navigation preferences in favor of a stimulus-response learning strategy. This has been hypothesized to result from competitive interactions of the caudate nucleus/dorsal striatum (DS) memory system with the hippocampus (HPC)-dependent spatial/allocentric memory system. In support of this hypothesis, a recent study reported that inactivation of the DS in aged rodents rescued HPC-dependent spatial learning on a T-maze (Gardner, Gold, & Korol, 2020). Currently, it is unclear whether a shift from HPC-dependent to DS-dependent behavior also contributes to age-related cognitive decline outside of spatial learning and memory. To test the hypothesis that inactivation of the DS can restore age-related cognitive function outside of spatial behavior, the present study bilaterally inactivated the DS of young (n = 8) and aged (n = 7) rats during visuospatial paired associates learning (PAL). This study found that inactivation of the DS did not alter PAL performance in young or aged rats, but did alter a positive control, DS-dependent spatial navigation task. This observation suggests that elevated DS activity does not play a role in the decline of HPC-dependent PAL performance in aged male rats. Given the persistent tendencies of aged rodents toward DS-dependent learning, it will be worthwhile to explore further the coordination dynamics between the HPC and DS that may contribute to age-related cognitive decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of bile duct ligation on the inhibitory control of supraoptic vasopressin neurons.

Dilutional hyponatremia due to increased plasma arginine vasopressin (AVP) is associated with liver cirrhosis. However, plasma AVP remains elevated despite progressive hypoosmolality. This study investigated changes to inhibitory control of supraoptic nucleus (SON) AVP neurons during liver cirrhosis. Experiments were conducted with adult male Sprague-Dawley rats. Bile duct ligation was used as a model of chronic liver cirrhosis. An adeno-associated virus containing a construct with an AVP promoter and either green fluorescent protein (GFP) or a ratiometric chloride indicator, ClopHensorN, was bilaterally injected into the SON of rats. After 2 weeks, rats received either BDL or sham surgery, and liver cirrhosis was allowed to develop for 4 weeks. In vitro, loose patch recordings of action potentials were obtained from GFP-labeled and unlabeled SON neurons in response to a brief focal application of the GABAA agonist muscimol (100 µM). Changes to intracellular chloride ([Cl]i) following muscimol application were determined by changes to the fluorescence ratio of ClopHensorN. The contribution of cation chloride cotransporters NKCC1 and KCC2 to changes in intracellular chloride was investigated using their respective antagonists, bumetanide (BU, 10 µM) and VU0240551 (10 µM). Plasma osmolality and hematocrit were measured as a marker of dilutional hyponatremia. The results showed reduced or absent GABAA -mediated inhibition in a greater proportion of AVP neurons from BDL rats as compared to sham rats (100% inhibition in sham vs. 47% in BDL, p = .001). Muscimol application was associated with increased [Cl]i in most cells from BDL as compared to cells from sham rats (χ2 = 30.24, p < .001). NKCC1 contributed to the impaired inhibition observed in BDL rats (p < .001 BDL - BU vs. BDL + BU). The results show that impaired inhibition of SON AVP neurons and increased intracellular chloride contribute to the sustained dilutional hyponatremia in liver cirrhosis.

Pharmacological evaluation of lateral habenula and rostromedial tegmental nucleus in the expression of ethanol-induced place preference.

Although ethanol administration produces a range of physiological effects, the rewarding aspect associated with its consumption is a major contributory factor to its abuse liability. Recently, lateral habenula (LHb) has been shown to be engaged by both rewarding and aversive stimuli. Its major glutamatergic output, the fasciculus retroflexus, projects to the rostromedial tegmental nucleus (RMTg) and controls the activity of the ventral tegmental area (VTA) dopaminergic system to promote reward circuitry. While several attempts have been made to understand the relationship between LHb and addiction, there is still a lack of knowledge in relation to ethanol addiction. In the present study, by pharmacologically exacerbating or inhibiting the LHb or RMTg neuronal activity during a post-conditioning test, we investigated the role of LHb-RMTg fasciculus retroflexus in ethanol-induced reward behavior using the conditioned place preference (CPP) test. We found that activation of LHb glutamatergic system by intra-LHb administration of l-trans-2,4-pyrrolidine dicarboxylate (PDC) (glutamate transporter inhibitor) significantly decreased CPP score; on the contrary, lamotrigine (inhibits glutamate release) significantly increased CPP score and showed a rewarding effect in CPP. Instead, intra-RMTg administration of muscimol (GABAA receptor agonist) significantly increased CPP score, whereas bicuculline (GABAA antagonist) treatment decreased CPP score. In immunohistochemistry, we found that PDC administration significantly decreased, whereas lamotrigine treatment significantly increased tyrosine hydroxylase immunoreactivity (TH-ir) in VTA and nucleus accumbens (NAc). Furthermore, while intra-RMTg administration of muscimol increased, the bicuculline treatment significantly decreased the TH-ir in VTA and NAc. Together, our behavioral and immunohistochemical results signify the role of LHb and RMTg in the expression of ethanol-conditioned reward behavior.

Quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition of the acoustic startle in rhesus macaques.

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABAA agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition.

Prelimbic cortex inactivation prevents ABA renewal based on satiety state.

We have previously shown that the rat prelimbic cortex (PL) is necessary for contexts to promote the performance of instrumental behaviors that have been learned in them, whether the context is physical (operant chamber) or behavioral (recent performance of a behavior that has historically preceded the target in a behavior chain). In the present experiment, we investigated the role of the PL in satiety level as an interoceptive acquisition context. Rats were trained to lever-press for sweet/fat pellets while sated (22 hrs continuous food access) followed by the extinction of the response while hungry (22 hrs food deprived). Pharmacological inactivation of the PL (with baclofen/muscimol infusion) attenuated renewal of the response that occurred upon a return to the sated context. In contrast, animals that received a vehicle (saline) infusion showed renewal of the previously extinguished response. These results support the hypothesis that the PL monitors the relevant contextual elements (physical, behavioral, or satiety state) associated with reinforcement of a response and promotes the subsequent performance of that response in their presence.

Acute and chronic convection-enhanced muscimol delivery into the rat subthalamic nucleus induces antiseizure effects associated with high responder rates.

Intracerebral drug delivery is an emerging treatment strategy aiming to manage seizures in patients with systemic drug-resistant epilepsies. In rat seizure and epilepsy models, the GABAA receptor agonist muscimol has shown powerful antiseizure potential when injected acutely into the subthalamic nucleus (STN), known for its capacity to provide remote control of different seizure types. However, chronic intrasubthalamic muscimol delivery required for long-term seizure suppression has not yet been investigated. We tested the hypothesis that chronic convection-enhanced delivery (CED) of muscimol into the STN produces long-lasting antiseizure effects in the intravenous pentylenetetrazole seizure threshold test in female rats. Acute microinjection was included to verify efficacy of intrasubthalamic muscimol delivery in this seizure model and caused significant antiseizure effects at 30 and 60 ng per hemisphere with a dose-dependent increase of responders and efficacy and only mild adverse effects compared to controls. For the chronic study, muscimol was bilaterally infused into the STN over three weeks at daily doses of 60, 300, or 600 ng per hemisphere using an implantable pump and cannula system. Chronic intrasubthalamic CED of muscimol caused significant long-lasting antiseizure effects for up to three weeks at 300 and 600 ng daily. Drug responder rate increased dose-dependently, as did drug tolerance rates. Transient ataxia and body weight loss were the main adverse effects. Drug distribution was comparable (about 2-3 mm) between acute and chronic delivery. This is the first study providing proof-of-concept that not only acute, but also chronic, continuous CED of muscimol into the STN raises seizure thresholds.

Execution of new trajectories toward a stable goal without a functional hippocampus.

The hippocampus is a critical component of a mammalian spatial navigation system, with the firing sequences of hippocampal place cells during sleep or immobility constituting a "replay" of an animal's past trajectories. A novel spatial navigation task recently revealed that such "replay" sequences of place fields can also prospectively map onto imminent new paths to a goal that occupies a stable location during each session. It was hypothesized that such "prospective replay" sequences may play a causal role in goal-directed navigation. In the present study, we query this putative causal role in finding only minimal effects of muscimol-induced inactivation of the dorsal and intermediate hippocampus on the same spatial navigation task. The concentration of muscimol used demonstrably inhibited hippocampal cell firing in vivo and caused a severe deficit in a hippocampal-dependent "episodic-like" spatial memory task in a watermaze. These findings call into question whether "prospective replay" of an imminent and direct path is actually necessary for its execution in certain navigational tasks.

Paroxysmal slow-wave discharges in a model of absence seizure are coupled to gamma oscillations in the thalamocortical and limbic systems.

OBJECTIVE: Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if gamma (30-160 Hz) activity were cross-frequency modulated by the 2-6 Hz slow-wave discharges induced by GBL in the limbic system. We hypothesized that inactivation of the nucleus reuniens (RE), which projects to frontal cortex (FC) and hippocampus, would affect the cross-frequency coupling of gamma (γ) in different brain regions. METHODS: Local field potentials were recorded by electrodes implanted in the FC, ventrolateral thalamus (TH), basolateral amygdala (BLA), nucleus accumbens (NAC), and dorsal hippocampus (CA1) of behaving rats. At each electrode, the coupling between the γ amplitude envelope to the phase of the 2-6 Hz slow-waves (SW) was measured by modulation index (MI) or cross-frequency coherence (CFC) of γ amplitude with SW. In separate experiments, the RE was infused with saline or GABAA receptor agonist, muscimol, before the injection of GBL. RESULTS: Following GBL injection, an increase in MI and CFC of SW to γ1 (30-58 Hz), γ2 (62-100 Hz) and γ3 (100-160 Hz) bands was observed at the FC, hippocampus and BLA, with significant increase in SW-γ1 and SW-γ3 coupling at TH, and increase in peak SW-γ1 CFC at NAC. Strong SW-γ modulation was also found during baseline immobility high-voltage spindles. Muscimol inactivation of RE, as compared to saline infusion, significantly decreased SW-γ1 CFC in the FC, and peak frequency of the SW-γ1 CFC in the thalamus, but did not significantly alter SW-γ CFCs in the hippocampus, BLA or NAC. SIGNIFICANCE: The paroxysmal 2-6 Hz SW discharges, a hallmark of absence seizure, significantly modulate γ activity in the hippocampus, BLA and NAC, suggesting a modulation of limbic functions. RE inactivation disrupted the SW modulation of FC and TH, partly supporting our hypothesis that RE participates in the modulation of SW discharges.

Sequential order spatial memory in male rats: Characteristics and impact of medial prefrontal cortex and hippocampus disruption.

Remembering an experience entails linking what happened, where the event transpired, and when it occurred. Most rodent hippocampal studies involve tests of spatial memory, but fewer investigate temporal and sequential order memory. Here we provide a demonstration of rats learning an aversive sequential order task using a radial arm water maze. Male rats learned a fixed sequence of up to seven spatial locations, with each decision session separated by a temporal delay. Rats relied on visuospatial cues and the number of times they had entered the maze for a given day in order to successfully perform the task. Behavioral patterns during asymptotic performance showed similarities to the serial-position effect, especially with regards to faster first choice latency. Rats at asymptotic performance were implanted with bilateral cannula in medial prefrontal cortex, dorsal, and ventral hippocampus. After re-training, we injected muscimol to temporarily disrupt targeted brain regions. While control rats made prospective errors, rats with mPFC muscimol exhibited more retrospective errors. Rats with hippocampal muscimol no longer exhibited a prospective bias and were at chance levels in their error choices. Taken together, our results suggest disruption of mPFC, but not the hippocampus, produced an error choice bias during an aversive sequential order spatial processing task.

Alteration of Lateral Habenula Function Prevents the Proper Exploration of a Novel Environment.

The lateral habenula (LHb) is an epithalamic brain region viewed as a converging hub, integrating information from a large connectome and then projecting to few critical midbrain monoaminergic systems. Numerous studies have explored the roles of the LHb, notably in aversion and avoidance. An important recurring finding when manipulating the LHb is the induction of anxiety-related behaviours. However, its exact role in such behaviours remains poorly understood. In the present study, we used two pharmacological approaches altering LHb activity, intra-LHb infusion of either the GABA-A receptor agonist, Muscimol, or the glutamatergic AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and exposed rats to three consecutive open field (OF) sessions. We found that both pharmacological treatments prevented rats to explore the centre of the OF, considered as the most anxiogenic part of the apparatus, across the three OF sessions. In addition, during the first, but not the two consecutive sessions, both treatments prevented a thorough exploration of the OF. Altogether, these results confirm the crucial role played by the LHb in anxiety-related behaviours and further suggest its implication in the exploration of new anxiogenic environments.