•The effects of stress on reversal learning in rats were assessed using touchscreen-equipped operant chambers.•Stress facilitated rates of late reversal learning after perseveration ...ceased.•Glucocorticoid receptor antagonism failed to block the effects of stress.•Glucocorticoid receptor antagonism significantly increased response but not reward latencies in the task.
The stress response is essential to the survival of all species as it maintains internal equilibrium and allows organisms to respond to threats in the environment. Most stress research has focused on the detrimental impacts of stress on cognition and behavior. Reversal learning, which requires a change in response strategy based on one dimension of the stimuli, is one type of behavioral flexibility that is facilitated following some brief stress procedures. The current study investigated a potential mechanism underlying this facilitation by blocking glucocorticoid receptors (GRs) during stress. Thirty-seven male Long Evans rats learned to discriminate between two images on a touchscreen, one of which was rewarded. Once a criterion was reached, rats received stress (30min of restraint stress or no stress) and drug (GR antagonist RU38486 or vehicle) administration prior to each of the first 3 days of reversal learning. We expected that stress would facilitate reversal learning and RU38486 (10mg/kg) would prevent this facilitation in both early (<50% correct in one session) and late (>50% correct in one session) stages of reversal learning. Results showed that stressed rats performed better than unstressed rats (fewer days for late reversal, fewer correction trials, and fewer errors) in the late but not early stage of reversal learning. RU38486 did not block the facilitation of RL by stress, although it dramatically increased response, but not reward, latencies. These results confirm the facilitation of late reversal by stress in a touchscreen-based operant task in rats and further our understanding of how stress affects higher level cognitive functioning and behavior.
The subiculum (SUB) serves as the major output structure of the hippocampus; therefore, exploring synaptic plasticity within this region is of great importance for understanding the dynamics of ...hippocampal circuitry and hippocampal-cortical interactions. Previous research has shown exposure to acute stress dramatically alters synaptic plasticity within the hippocampus proper. Using in vivo electrophysiological recordings in urethane-anesthetized adult male Sprague-Dawley rats, we tested the effects of either acute restraint stress (30 min) or corticosterone (CORT) injections (3 mg/kg; s.c.) on short- and long-term forms of synaptic plasticity in the Cornu Ammonis 1-SUB pathway. Paired-pulse facilitation and two forms of long-term plasticity (long-term potentiation and late-developing potentiation) were significantly reduced after exposure to acute stress but not CORT treatment. Measurements of plasma CORT confirmed similar levels of circulating hormone in animals exposed to either acute stress or CORT treatment. The disruptive effects of acute stress on both short- and long-term forms of synaptic plasticity are mediated by glucocorticoid receptor (GR) activation as these disruptions were blocked by pre-treatment with the selective GR antagonist RU38486 (10 mg/kg; s.c.). The present results highlight the susceptibility of subicular plasticity to acute stress and provide evidence that GR activation is necessary but not sufficient for mediating these alterations.
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.
The trial-unique, delayed nonmatching-to-location (TUNL) task is a recently developed behavioral task that measures spatial working memory and a form of pattern separation in touchscreen-equipped ...operant conditioning chambers. Limited information exists regarding the neurotransmitters and neural substrates involved in the task. The present experiments tested the effects of systemic and intracranial injections of NMDA receptor antagonists on the TUNL task. After training, male Long Evans rats systemically injected with the competitive NMDA receptor antagonist CPP (10 mg/kg) had impaired accuracy regardless of the degree of stimuli separation or length of delay between the sample and test phases. Injections of Ro 25-6981 (6 or 10 mg/kg), an antagonist selective for GluN2B subunit-containing NMDA receptors, did not affect accuracy on the task. Direct infusion of the competitive NMDA receptor antagonist AP5 into mPFC or dmSTR reduced overall accuracy on the TUNL task. These results demonstrate that TUNL task performance depends on NMDA receptors within the mPFC and dmSTR.
•Male and female GAERS show social interaction deficits.•The T-type calcium channel antagonist Z944 reverses some social deficits in GAERS.•Z944 decreases introductory and aggressive behaviors in ...GAERS and control rats.•Z944 increases anxiety behaviors in GAERS in an open field and elevated plus maze.
Abnormalities in social behavior are a co-morbid symptom of idiopathic generalized epilepsies such as childhood absence epilepsy. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model is a spontaneously occurring absence epilepsy phenotype closely correlated to that of human absence epilepsies. Similar to the human conditions, GAERS display social abnormalities. Previous studies have only demonstrated social abnormalities in female GAERS, whereas social problems are observed in male and female patients. Seizures in GAERS result in part due to a gain-of-function missense mutation in the Cav3.2 T-type calcium channel gene. This study examined the effects of the pan-T-type calcium channel antagonist, Z944, on social interaction behaviors in male and female GAERS using an open field social interaction test. A second objective of this study was to examine the effects of Z944 on anxiety-like behavior in an open field locomotion test and elevated plus maze. Results showed a decrease in social activity in GAERS relative to non-epileptic control (NEC) rats. Acute, systemic Z944 (5 mg/kg; i.p.) consistently reduced introductory and aggressive behaviors in both GAERS and NECs whereas strain effects were observed for over-and-under crawl behaviors. In the open field locomotion test and elevated plus maze, Z944 increased anxiety-like behaviors in GAERS, whereas, Z944 produced inconsistent effects on anxiety-like behaviors in NECs. The results of this study suggest that the regulation of T-type calcium channel activity may be a useful strategy for the development of new therapeutic approaches for the treatment of social and affective abnormalities observed in absence epilepsy disorders.
Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are a rodent model of childhood absence epilepsy (CAE) that display a gain‐of‐function mutation in the gene encoding the Cav3.2 T‐type calcium ...channel. GAERS demonstrate heightened learning and delayed extinction of fear conditioning. Our objective in the present study was to examine the effects of the pan‐T‐type calcium channel blocker Z944 on the acquisition, consolidation and extinction of conditioned fear in GAERS and the non‐epileptic control (NEC) strain. Z944 (10 mg/kg; ip) was administered 15 min prior to either acquisition, extinction day 1 (24 hr later), acquisition and extinction day 1, or during the consolidation (post‐acquisition) of tone‐cued fear conditioning. Extinction was examined 24 and 48 hr after conditioning. In drug naïve GAERS, increased freezing during the acquisition and extinction phases of fear conditioning was found. Short‐term effects of Z944 on performance were observed as Z944 increased freezing during testing on the day it was administered. Z944 administered prior to the acquisition phase had a long‐term effect on extinction. Specifically, both GAERS and NECs showed a decrease in freezing during extinction relative to drug naïve GAERS and NEC rats respectively. Regardless of strain or treatment, female rats showed reduced extinction of fear relative to male rats. These results demonstrate that T‐type calcium channels contribute to the neural systems that mediate the learning and memory of conditioned fear. Overall, these findings suggest that T‐type calcium channel blockers show promise in the treatment of learning impairments observed in disorders such as CAE.
Treatment with the T‐type calcium channel blocker Z944 prior to the acquisition of fear conditioning decreased freezing in Genetic Absence Epilepsy Rats from Strasbourg during the extinction phases to levels comparable to non‐epileptic controls (NECs). NECs treated with Z944 also showed reduced freezing during extinction; however, the results suggest that NECs have impaired recall of conditioned fear as little freezing behaviour was observed during extinction trials.
Rationale
New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities ...that may be useful in treating some aspects of the cognitive symptoms of the disorder.
Objective
The objective of the present studies was to test the effects of the
d
- and
l
-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound.
Methods
MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg),
d
- and
l
-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers.
Results
Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials.
l
-Govadine (1.0 mg/kg), but not
d
-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of
l
-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes.
Conclusion
l
-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of
l
-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.
•Z944 administered before fear conditioning increased freezing during acquisition.•Recall of conditioned fear was impaired by Z944 administration before acquisition.•Z944 administered before fear ...recall had no effect on extinction.
The T-type calcium channel blocker, Z944, has been used as a pharmacological tool to assess T-type calcium channel function and examined for use as an anti-epileptic. As Z944 affects fear learning and memory in a rodent model of absence epilepsy, it is important to determine the effect of Z944 on learning and memory in a non-disease outbred rodent strain. This study examined the dose-dependent effects (5 mg/kg, 10 mg/kg, i.p.) of acute systemic treatment with Z944 on the learning and memory of fear conditioning and extinction in male Wistar rats. Z944 administered prior to the acquisition of fear conditioning significantly increased freezing prior to acquisition and extinction, during acquisition, and impaired recall of fear memory 24 h later. These findings suggest that T-type calcium channel activity may be required during associative learning for intact long-term memory. Enhanced fear behaviour observed prior to acquisition and extinction, and during acquisition could reflect an increase in anxiety, however, further testing is needed to determine the effect of Z944 on anxiety during fear conditioning and extinction. The use of Z944 for therapeutic purposes should consider the potential effects of Z944 on learning and memory in clinical populations.
Sex differences are documented in psychiatric and neurological disorders, yet most preclinical animal research has been conducted in males only. There is a need to better understand of the nature of ...sex differences in brain disease in order to meet the needs of psychiatric patients. We present the behavior profile of adult female offspring produced using a maternal immune activation (MIA) model where pregnant rats receive an immune stimulant and the offspring typically show various abnormalities consistent with psychiatric illnesses such as schizophrenia and autism. The results in female offspring were compared to a previously published cohort of their male siblings (Lins et al., 2018). We examined prepulse inhibition (PPI), sociability, MK-801-induced locomotor activity, crossmodal object recognition (CMOR), and oddity discrimination; behaviors relevant to the positive, negative, and cognitive symptoms of schizophrenia. No between-treatment differences in PPI or locomotor activity were noted. Tactile memory was observed in the control and treated female offspring, visual recognition memory was deficient in the polyinosinic:polycytidylic acid (polyI:C) offspring only, and both groups lacked crossmodal recognition. PolyI:C offspring were impaired in oddity preference and had reduced preference for a stranger conspecific in a sociability assay. Systemic maternal CXCL1, IL-6, and TNF-a levels 3 h after polyI:C treatment were determined, but no relationship was found between these cytokines and the behavior seen in the adult female offspring. Overall, female offspring of polyI:C-treated dams display an array of behavior abnormalities relevant to psychiatric illnesses such as schizophrenia similar to those previously reported in male rats.
•Acute MK-801 treatment impairs paired associates learning, a visual-spatial memory task.•mGluR5 positive allosteric modulator CDPPB has no consistent effects on PAL in well-trained rats.•CDPPB was ...ineffective at reversing the MK-801 induced impairments in PAL.
Effective treatments for the cognitive symptoms of schizophrenia are critically needed. Positive allosteric modulation (PAM) of metabotropic glutamate receptor subtype 5 (mGluR5) is one strategy currently under investigation to improve these symptoms. Examining cognition using touchscreen-equipped operant chambers may increase translation between preclinical and clinical research through analogous behavioral testing paradigms in rodents and humans. We used acute CDPPB (1–30mg/kg) treatment to examine the effects of mGluR5 PAM in the touchscreen paired associates learning (PAL) task using well-trained rats with and without co-administration of acute MK-801 (0.15mg/kg). CDPPB had no consistent effects on task performance when administered alone and failed to reverse the MK-801 induced impairments at any of the examined doses. Overall, the disruptive effects of MK-801 on PAL were consistent with previous research but increasing mGluR5 signaling is not beneficial in the PAL task. Future research should test whether administration of CDPPB during PAL acquisition increases performance.
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