Therapeutic potential of gamma entrainment using sensory stimulation for cognitive symptoms associated with schizophrenia.

Schizophrenia is a complex neuropsychiatric disorder with significant morbidity. Treatment options that address the spectrum of symptoms are limited, highlighting the need for innovative therapeutic approaches. Gamma Entrainment Using Sensory Stimulation (GENUS) is an emerging treatment for neuropsychiatric disorders that uses sensory stimulation to entrain impaired oscillatory network activity and restore brain function. Aberrant oscillatory activity often underlies the symptoms experienced by patients with schizophrenia. We propose that GENUS has therapeutic potential for schizophrenia. This paper reviews the current status of schizophrenia treatment and explores the use of sensory stimulation as an adjunctive treatment, specifically through gamma entrainment. Impaired gamma frequency entrainment is observed in patients, particularly in response to auditory and visual stimuli. Thus, sensory stimulation, such as music listening, may have therapeutic potential for individuals with schizophrenia. GENUS holds novel therapeutic potential to improve the lives of individuals with schizophrenia, but further research is required to determine the efficacy of GENUS, optimize its delivery and therapeutic window, and develop strategies for its implementation in specific patient populations.

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 (GABAA/B 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.

Evidence for novelty reward cross-cueing in the odor span task in rats: implications for odor-based reward-motivated tasks.

The odor span task (OST) infers working memory capacity (WMC) by requiring rodents to discriminate between previously presented and session-novel odors to obtain a hidden food reward. Here, rats' responses to session-novel odors and food rewards were assessed to determine whether rats use mitigating strategies in the OST. Rats accurately responded to session-novel odors but also reliably responded to the food reward alone and performed at chance when both a session-novel odor and food reward were presented in separate locations. The inclusion of unscented sand in the cups holding the food reward significantly reduced the rats' responses to the food reward alone. Collectively, these results demonstrate the need for rigorous tests of potential mitigating strategies and hold wide implications for rodent odor discrimination-based behavioral tasks.

Nucleus accumbens core dopamine D2 receptors are required for performance of the odor span task in male rats.

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.

Repeated Exposure to High-THC Cannabis Smoke during Gestation Alters Sex Ratio, Behavior, and Amygdala Gene Expression of Sprague Dawley Rat Offspring.

Because of the legalization of Cannabis in many jurisdictions and the trend of increasing Δ9-tetrahydrocannabinol (THC) content in Cannabis products, an urgent need exists to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we exposed female Sprague Dawley rats to Cannabis smoke daily from gestational day 6 to 20 or room air. Maternal reproductive parameters, offspring behavior, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis-exposed litters. In adulthood, male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. Gestational Cannabis smoke exposure did not affect behavior on the elevated plus maze test or social interaction test in the offspring. Cannabis offspring were better at visual pairwise discrimination and reversal learning tasks conducted in touchscreen-equipped operant conditioning chambers. Analysis of gene expression in the adult amygdala using RNA sequencing revealed subtle changes in genes related to development, cellular function, and nervous system disease in a subset of the male offspring. These results demonstrate that repeated exposure to high-THC Cannabis smoke during gestation alters maternal physiological parameters, sex ratio, and anxiety-like behaviors in the adulthood offspring.

High-THC Cannabis Smoke Impairs Incidental Memory Capacity in Spontaneous Tests of Novelty Preference for Objects and Odors in Male Rats.

Working memory is an executive function that orchestrates the use of limited amounts of information, referred to as working memory capacity, in cognitive functions. Cannabis exposure impairs working memory in humans; however, it is unclear whether Cannabis facilitates or impairs rodent working memory and working memory capacity. The conflicting literature in rodent models may be at least partly because of the use of drug exposure paradigms that do not closely mirror patterns of human Cannabis use. Here, we used an incidental memory capacity paradigm where a novelty preference is assessed after a short delay in spontaneous recognition-based tests. Either object or odor-based stimuli were used in test variations with sets of identical [identical stimuli test (IST)] and different [different stimuli test (DST)] stimuli (three or six) for low-memory and high-memory loads, respectively. Additionally, we developed a human-machine hybrid behavioral quantification approach which supplements stopwatch-based scoring with supervised machine learning-based classification. After validating the spontaneous IST and DST in male rats, 6-item test versions with the hybrid quantification method were used to evaluate the impact of acute exposure to high-Δ9-tetrahydrocannabinol (THC) or high-CBD Cannabis smoke on novelty preference. Under control conditions, male rats showed novelty preference in all test variations. We found that high-THC, but not high-CBD, Cannabis smoke exposure impaired novelty preference for objects under a high-memory load. Odor-based recognition deficits were seen under both low-memory and high-memory loads only following high-THC smoke exposure. Ultimately, these data show that Cannabis smoke exposure impacts incidental memory capacity of male rats in a memory load-dependent, and stimuli-specific manner.

Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure.

Cannabis sativa has gained popularity as a "natural substance", leading many to falsely assume that it is not harmful. This assumption has been documented amongst pregnant mothers, many of whom consider Cannabis use during pregnancy as benign. The purpose of this study was to validate a Cannabis smoke exposure model in pregnant rats by determining the plasma levels of cannabinoids and associated metabolites in the dams after exposure to either Cannabis smoke or injected cannabinoids. Maternal and fetal cytokine and chemokine profiles were also assessed after exposure. Pregnant Sprague-Dawley rats were treated daily from gestational day 6-20 with either room air, i.p. vehicle, inhaled high-Δ9-tetrahydrocannabinol (THC) (18% THC, 0.1% cannabidiol [CBD]) smoke, inhaled high-CBD (0.7% THC, 13% CBD) smoke, 3 mg/kg i.p. THC, or 10 mg/kg i.p. CBD. Our data reveal that THC and CBD, but not their metabolites, accumulate in maternal plasma after repeated exposures. Injection of THC or CBD was associated with fewer offspring and increased uterine reabsorption events. For cytokines and chemokines, injection of THC or CBD up-regulated several pro-inflammatory cytokines compared to control or high-THC smoke or high-CBD smoke in placental and fetal brain tissue, whereas smoke exposure was generally associated with reduced cytokine and chemokine concentrations in placental and fetal brain tissue compared to controls. These results support existing, but limited, knowledge on how different routes of administration contribute to inconsistent manifestations of cannabinoid-mediated effects on pregnancy. Smoked Cannabis is still the most common means of human consumption, and more preclinical investigation is needed to determine the effects of smoke inhalation on developmental and behavioural trajectories.

MEPIRAPIM-derived synthetic cannabinoids inhibit T-type calcium channels with divergent effects on seizures in rodent models of epilepsy.

Background: T-type Ca2+ channels (Cav3) represent emerging therapeutic targets for a range of neurological disorders, including epilepsy and pain. To aid the development and optimisation of new therapeutics, there is a need to identify novel chemical entities which act at these ion channels. A number of synthetic cannabinoid receptor agonists (SCRAs) have been found to exhibit activity at T-type channels, suggesting that cannabinoids may provide convenient chemical scaffolds on which to design novel Cav3 inhibitors. However, activity at cannabinoid type 1 (CB1) receptors can be problematic because of central and peripheral toxicities associated with potent SCRAs. The putative SCRA MEPIRAPIM and its analogues were recently identified as Cav3 inhibitors with only minimal activity at CB1 receptors, opening the possibility that this scaffold may be exploited to develop novel, selective Cav3 inhibitors. Here we present the pharmacological characterisation of SB2193 and SB2193F, two novel Cav3 inhibitors derived from MEPIRAPIM. Methods: The potency of SB2193 and SB2193F was evaluated in vitro using a fluorometric Ca2+ flux assay and confirmed using whole-cell patch-clamp electrophysiology. In silico docking to the cryo-EM structure of Cav3.1 was also performed to elucidate structural insights into T-type channel inhibition. Next, in vivo pharmacokinetic parameters in mouse brain and plasma were determined using liquid chromatography-mass spectroscopy. Finally, anticonvulsant activity was assayed in established genetic and electrically-induced rodent seizure models. Results: Both MEPIRAPIM derivatives produced potent inhibition of Cav3 channels and were brain penetrant, with SB2193 exhibiting a brain/plasma ratio of 2.7. SB2193 was further examined in mouse seizure models where it acutely protected against 6 Hz-induced seizures. However, SB2193 did not reduce spontaneous seizures in the Scn1a +/- mouse model of Dravet syndrome, nor absence seizures in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Surprisingly, SB2193 appeared to increase the incidence and duration of spike-and-wave discharges in GAERS animals over a 4 h recording period. Conclusion: These results show that MEPIRAPIM analogues provide novel chemical scaffolds to advance Cav3 inhibitors against certain seizure types.

Formation and fate of an engram in the lateral amygdala supporting a rewarding memory in mice.

Memories allow past experiences to guide future decision making and behavior. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Most previous research has focused on engrams supporting threatening or fearful memories where results show that neurons involved in a particular engram ("engram neurons") are both necessary and sufficient for memory expression. Far less is understood about engrams supporting appetitive or rewarding memories. As circumstances and environments are dynamic, the fate of a previously acquired engram with changing circumstances is unknown. Here we examined how engrams supporting a rewarding cue-cocaine memory are formed and whether this original engram is important in reinstatement of memory-guided behavior following extinction. Using a variety of techniques, we show that neurons in the lateral amygdala are allocated to an engram based on relative neuronal excitability at training. Furthermore, once allocated, these neurons become both necessary and sufficient for behavior consistent with recall of that rewarding memory. Allocated neurons are also critical for cocaine-primed reinstatement of memory-guided behavior following extinction. Moreover, artificial reactivation of initially allocated neurons supports reinstatement-like behavior following extinction even in the absence of cocaine-priming. Together, these findings suggest that cocaine priming after extinction reactivates the original engram, and that memory-guided reinstatement behavior does not occur in the absence of this reactivation. Although we focused on neurons in one brain region only, our findings that manipulations of lateral amygdala engram neurons alone were sufficient to impact memory-guided behavior indicate that the lateral amygdala is a critical hub region in what may be a larger brain-wide engram.

After the virus has cleared-Can preclinical models be employed for Long COVID research?

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.

Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease.

During chronic infection, the single celled parasite, Toxoplasma gondii, can migrate to the brain where it has been associated with altered dopamine function and the capacity to modulate host behavior, increasing risk of neurocognitive disorders. Here we explore alterations in dopamine-related behavior in a new mouse model based on stimulant (cocaine)-induced hyperactivity. In combination with cocaine, infection resulted in heightened sensorimotor deficits and impairment in prepulse inhibition response, which are commonly disrupted in neuropsychiatric conditions. To identify molecular pathways in the brain affected by chronic T. gondii infection, we investigated patterns of gene expression. As expected, infection was associated with an enrichment of genes associated with general immune response pathways, that otherwise limits statistical power to identify more informative pathways. To overcome this limitation and focus on pathways of neurological relevance, we developed a novel context enrichment approach that relies on a customized ontology. Applying this approach, we identified genes that exhibited unexpected patterns of expression arising from the combination of cocaine exposure and infection. These include sets of genes which exhibited dampened response to cocaine in infected mice, suggesting a possible mechanism for some observed behaviors and a neuroprotective effect that may be advantageous to parasite persistence. This model offers a powerful new approach to dissect the molecular pathways by which T. gondii infection contributes to neurocognitive disorders.

The effects of acute Cannabis smoke or Δ9-THC injections on the trial-unique, nonmatching-to-location and five-choice serial reaction time tasks in male Long-Evans rats.

Executive functions including working memory (WM) and attention are altered following Cannabis exposure in humans. To test for similar effects in a rodent model, we exposed adult male rats to acute Cannabis smoke before testing them on touchscreen-based tasks that assess these executive processes. The trial-unique, delayed nonmatching-to-location (TUNL) task was used to evaluate WM, task performance at different spatial pattern separations, and response latencies. The five-choice serial reaction time task (5-CSRTT) was used to measure attention, impulsivity, perseveration, and response latencies. Rats were exposed acutely to high- Δ9-tetrahydrocannabinol (THC), low-CBD (Mohawk) and low-THC, high-CBD (Treasure Island) strains of Cannabis smoke using a chamber inhalation system. The effects of Cannabis smoke were directly compared to systemic Δ9-THC injection (3.0 mg/kg; i.p.). TUNL task performance was significantly impaired following acute high-THC smoke exposure or THC injections, but not low-THC smoke exposure, with no effects on response latencies. Fewer total trials and selection trials were also performed following THC injections. Performance was poorer for smaller separation distances in all groups. Neither acute smoke exposure, nor injected THC, impacted attentional processes, impulsivity, perseverations, or response latencies in the 5-CSRTT. Pharmacokinetic analysis of rat plasma revealed significantly higher THC levels following injections than smoke exposure 30 min following treatment. Exposure to low-THC, high-CBD Cannabis smoke significantly increased CBD in plasma, relative to the other treatments. Taken together, our results suggest that WM processes as measured by the TUNL task are more sensitive to THC exposure than the attentional and impulsivity measures assessed using the 5-CSRTT.

The type 1 cannabinoid receptor positive allosteric modulators GAT591 and GAT593 reduce spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg.

Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5-5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS. In vitro experiments confirm that GAT591 and GAT593 exhibit increased potency and selectivity in cell cultures and behave as CB1R allosteric agonists and PAMs. To assess drug effects on SWDs, bilateral electrodes were surgically implanted in the somatosensory cortices of male GAERS and EEGs recorded for 4 h following systemic administration of GAT591 or GAT593 (1.0, 3.0 and 10.0 mg/kg). Both GAT591 and GAT593 dose-dependently reduced total SWD duration during the recording period. The greatest effect on SWD activity was observed at 10.0 mg/kg doses, with GAT591 and GAT593 reducing seizure duration by 36% and 34% respectively. Taken together, these results support the continued investigation of CB1R PAMs as a potential therapeutic to alleviate SWDs in absence epilepsy.

The rodent medial prefrontal cortex and associated circuits in orchestrating adaptive behavior under variable demands.

Emerging evidence implicates rodent medial prefrontal cortex (mPFC) in tasks requiring adaptation of behavior to changing information from external and internal sources. However, the computations within mPFC and subsequent outputs that determine behavior are incompletely understood. We review the involvement of mPFC subregions, and their projections to the striatum and amygdala in two broad types of tasks in rodents: 1) appetitive and aversive Pavlovian and operant conditioning tasks that engage mPFC-striatum and mPFC-amygdala circuits, and 2) foraging-based tasks that require decision making to optimize reward. We find support for region-specific function of the mPFC, with dorsal mPFC and its projections to the dorsomedial striatum supporting action control with higher cognitive demands, and ventral mPFC engagement in translating affective signals into behavior via discrete projections to the ventral striatum and amygdala. However, we also propose that defined mPFC subdivisions operate as a functional continuum rather than segregated functional units, with crosstalk that allows distinct subregion-specific inputs (e.g., internal, affective) to influence adaptive behavior supported by other subregions.

Dissociable changes in spike and wave discharges following exposure to injected cannabinoids and smoked cannabis in Genetic Absence Epilepsy Rats from Strasbourg.

There is significant interest in the use of cannabinoids for the treatment of many epilepsies including absence epilepsy (AE). Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model many aspects of AE including the presence of spike-and-wave discharges (SWDs) on electroencephalogram (EEG) and behavioral comorbidities, such as elevated anxiety. However, the effects of cannabis plant-based phytocannabinoids have not been tested in GAERS. Therefore, we investigated how SWDs in GAERS are altered by the two most common phytocannabinoids, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), and exposure to smoke from two different chemovars of cannabis. Animals were implanted with bipolar electrodes in the somatosensory cortex and EEGs were recorded for 2 hr. Injected THC (1-10 mg/kg, i.p.) dose-dependently increased SWDs to over 200% of baseline. In contrast, CBD (30-100 mg/kg, i.p.) produced a ~50% reduction in SWDs. Exposure to smoke from a commercially available chemovar of high-THC cannabis (Mohawk, Aphria Inc.) increased SWDs whereas a low-THC/high-CBD chemovar of cannabis (Treasure Island, Aphria Inc.) did not significantly affect SWDs in GAERS. Pre-treatment with a CB1R antagonist (SR141716A) did not prevent the high-THC cannabis smoke from increasing SWDs, suggesting that the THC-mediated increase may not be CB1R-dependent. Plasma concentrations of THC and CBD were similar to previously reported values following injection and smoke exposure. Compared to injected CBD, it appears Treasure Island did not increase plasma levels sufficiently to observe an anti-epileptic effect. Together these experiments provide initial evidence that acute phytocannabinoid administration exerts the biphasic modulation of SWDs and may differentially impact patients with AE.

The Touchscreen-Based Trial-Unique, Nonmatching-To-Location (TUNL) Task as a Measure of Working Memory and Pattern Separation in Rats and Mice.

The TUNL task is an automated touchscreen task used to evaluate the cognitive processes involved in working memory (WM) and spatial pattern separation in rodents. Both rats and mice can be used. To elicit working memory processes, the rodent must distinguish between a sample (familiar) light stimulus and a novel light stimulus after a delay. With a correct selection, the rodent will receive a food reward. A major benefit of TUNL compared to other similar tasks is the circumvention of spatial "mediating strategies" that the rodent may use to supplement or replace working memory processes to complete the task successfully. Each trial is 'unique', as the stimuli are pseudo-randomized between trials in an array of spatial locations. The TUNL task uses a progression of six training steps to teach the rodent the associated rules necessary to complete the full task. Task performance is typically measured by trials completed and by accuracy. Task accuracy can be evaluated across various spatial separations to engage hippocampal-dependent processes involved in spatial pattern separation. The latency between trial responses can also be evaluated, with food reward collection latency as a measure of motivation. The TUNL task can be used to assess working memory and cognitive deficits in rodent models with neurodegenerative and neurological disorders, providing a valuable tool to screen for new treatment options, in addition to assessing basic neurobiology. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Handling and habituation prior to training Basic Protocol 2: Initial Touch Training Basic Protocol 3: Must Touch Training Basic Protocol 4: Must Initiate Training Basic Protocol 5: Punish Incorrect Training Basic Protocol 6: Initial TUNL Training Basic Protocol 7: Full TUNL Training Support Protocol 1: Using ABET II touch program Support Protocol 2: Preparation of touchscreen chambers prior to training sessions.

Adult neurogenesis mediates forgetting of multiple types of memory in the rat.

The formation and retention of hippocampus-dependent memories is impacted by neurogenesis, a process that involves the production of new neurons in the dentate gyrus of the hippocampus. Recent studies demonstrate that increasing neurogenesis after memory formation induces forgetting of previously acquired memories. Neurogenesis-induced forgetting was originally demonstrated in mice, but a recent report suggests that the same effect may be absent in rats. Although a general species difference is possible, other potential explanations for these incongruent findings are that memories which are more strongly reinforced become resilient to forgetting or that perhaps only certain types of memories are affected. Here, we investigated whether neurogenesis-induced forgetting occurs in rats using several hippocampus-dependent tasks including contextual fear conditioning (CFC), the Morris Water Task (MWT), and touchscreen paired associates learning (PAL). Neurogenesis was increased following training using voluntary exercise for 4 weeks before recall of the previous memory was assessed. We show that voluntary running causes forgetting of context fear memories in a neurogenesis-dependent manner, and that neurogenesis-induced forgetting is present in rats across behavioral tasks despite differences in complexity or reliance on spatial, context, or object memories. In addition, we asked whether stronger memories are less susceptible to forgetting by varying the strength of training. Even with a very strong training protocol in the CFC task, we still observed enhanced forgetting related to increased neurogenesis. These results suggest that forgetting due to neurogenesis is a conserved mechanism that aids in the clearance of memories.

Altered acoustic startle, prepulse facilitation, and object recognition memory produced by corticosterone withdrawal in male rats.

The symptoms of human depression often include cognitive deficits. However, cognition is not frequently included in the behavioral assessments conducted in preclinical models of depression. For example, it is well known that repeated corticosterone (CORT) injections in rodents produce depression-like behavior as measured by the forced swim test, sucrose preference test, and tail suspension test, but the cognitive impairments produced by repeated CORT have not been thoroughly examined. The purpose of this experiment was to assess the effect of repeated CORT injections on several versions of object recognition memory and modulation of the acoustic startle response by relatively low intensity prepulses, along with the more traditional assessment of depression-like behavior using the forced swim test. Rats received 21 days of CORT (40 mg/kg) or vehicle injections followed by a battery of behavioral tests. Importantly, during behavioral testing CORT treatment did not occur (CORT withdrawal). Corticosterone decreased body weight, increased immobility in the forced swim test, lowered startle amplitudes, and facilitated responding to trials with a short interval (30 ms) between the prepulse and pulse. Corticosterone also impaired both object location and object-in-place recognition memory, while sparing performance on object recognition memory. Collectively, our data suggest that CORT produces selective disruptions in prepulse facilitation, object location, and object-in-place recognition memory, and that these impairments should be considered as part of the phenotype produced by repeated CORT, and perhaps chronic stress.

Positive allosteric modulation of type 1 cannabinoid receptors reduces spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg.

Childhood Absence Epilepsy (CAE) accounts for approximately 10% of all pediatric epilepsies. Current treatments for CAE are ineffective in approximately 1/3 of patients and can be associated with severe side effects such as hepatotoxicity. Certain cannabinoids, such as cannabidiol (CBD), have shown promise in the treatment of pediatric epilepsies. However, CBD remains limited or prohibited in many jurisdictions, and has not been shown to have efficacy in CAE. Modulation of the type 1 cannabinoid receptor (CB1R) may provide more desirable pharmacological treatments. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model many aspects of CAE, including cortical spike and wave discharges (SWDs). We have recently demonstrated that Δ9-tetrahydrocannabinol (THC) increases SWDs in GAERS whereas CBD decreases these events. Here, we characterized aspects of the endocannabinoid system in brain areas relevant to seizures in GAERS and tested whether positive allosteric modulators (PAMs) of CB1R reduced SWDs. Both female and male GAERS had reduced (>50%) expression of CB1R and elevated levels of the endocannabinoid 2-AG in cortex compared to non-epileptic controls (NEC). We then administered the CB1R PAMs GAT211 and GAT229 to GAERS implanted with cortical electrodes. Systemic administration of GAT211 to male GAERS reduced SWDs by 40%. Systemic GAT229 administration reduced SWDs in female and male GAERS. Intracerebral infusion of GAT229 into the cortex of male GAERS reduced SWDs by >60% in a CB1R-dependent manner that was blocked by SR141716A. Together, these experiments identify altered endocannabinoid tone in GAERS and suggest that CB1R PAMs should be explored for treatment of absence seizures.

Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies.

RATIONALE: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. OBJECTIVES: This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. METHODS: The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. RESULTS: GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. CONCLUSION: Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.