Robert E. Featherstone

Gestational methylazoxymethanol acetate treatment impairs select cognitive functions : Parallels to schizophrenia

Gestational methylazoxymethanol acetate (MAM) exposure has been suggested to produce neural and behavioral abnormalities similar to those seen in schizophrenia. In order to assess MAM treatment as a model of schizophrenia, pregnant female rats were injected with MAM (22 mg/kg) on gestational day 17 and their offspring were assessed in adulthood on a series of cognitive tasks. The first experiment involved an attentional set-shifting task, a rodent analog of the Wisconsin card sort task. In experiment 2, animals were tested on the 5-choice serial reaction time task, a rodent analog of the continuous performance task. In the final experiment animals were assessed on a differential reinforcement of low rate of responding 20 s schedule of reinforcement (DRL-20), a task that is sensitive to changes in inhibitory control. In the first experiment, MAM-treated animals required a greater number of trials than controls to successfully learn an extradimensional shift on the set-shifting task, and had difficulties in learning to reverse a previously acquired discrimination. In contrast, MAM-treated animals showed little impairment on the 5-choice task, aside from a modest but consistent increase in premature responding. Finally, MAM exposed animals showed substantial impairments in DRL performance. Post-mortem analysis of brain tissue showed significant decreases in tissue weight in the hippocampus, parietal cortex, prefrontal cortex, and dorsal striatum of MAM-treated animals. These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition.

Dorsal striatum and stimulus–response learning: lesions of the dorsolateral, but not dorsomedial, striatum impair acquisition of a simple discrimination task

In the present experiment, the effects of neurotoxic lesions (quinolinic acid) of the dorsolateral or dorsomedial striatum were investigated on a simple instrumental discrimination task (CS+/CS-). Rats with lesions of the dorsolateral striatum were found to be impaired in the acquisition of this task, as compared to rats with either dorsomedial striatal or sham lesions. Furthermore, dorsolateral striatal lesioned animals had significantly lower levels of responding across the course of discrimination training, as assessed both by overall rate of response during CS+ presentations and number of CS+ trials without a response, despite having shown levels of responding during variable interval training that did not differ from that of sham lesioned animals. In contrast, animals with lesions of the dorsomedial striatum did not show an impairment in acquisition of the present task, but had slightly higher rates of responding during CS- presentations. It is argued that the poor acquisition and low response rates observed in animals with dorsolateral striatal lesions reflect a failure in stimulus-response learning, while the performance of animals with dorsomedial striatal lesions may have been the result of an increase in overall activity rate.

Plasticity in the maternal circuit: effects of experience and partum condition on brain astrocyte number in female rats.

Female rats that have received a maternal experience undergo enhanced c-fos expression in a number of brain sites when reexposed to pups. The present 2 studies examined changes in the expression of another brain protein, glial fibrillary acidic protein (GFAP), which is a major unit of the astrocytic cytoskeleton. In both experiments, primiparous and multiparous female rats were given varying amounts of postpartum contact with pups and overdosed after varying intervals, with no pups. Brains were prepared for GFAP immunohistochemical analysis. In both studies, Day 5 postpartum multiparous subjects given additional postpartum contact with pups, when compared with pup-exposed primiparous subjects, were found to have significantly higher numbers of GFAP positive cells in the medial preoptic area of the hypothalamus, an area critical for the expression of maternal behavior, but not in control sites. In Experiment 2, an opposite effect of parity was found in the medial amygdala and habenula.

Parvalbumin Cell Ablation of NMDA-R1 Causes Increased Resting Network Excitability with Associated Social and Self-Care Deficits

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.

A sensitizing regimen of amphetamine that disrupts attentional set-shifting does not disrupt working or long-term memory

Exposure to an intermittent, escalating dose of amphetamine induces a sensitized state that, both behaviourally and neurochemically, mirrors several features linked to the positive symptoms of schizophrenia. Increasingly it is being realized that cognitive deficits are a core component of schizophrenia; therefore we sought to assess the effects of inducing an amphetamine-sensitized state on memory (working and long-term) and cognitive flexibility, two cognitive domains impaired in schizophrenia. Rats were exposed to a sensitizing regimen of amphetamine (1-5 mg/kg; three times per week for 5 weeks; escalating at 1mg/kg per week) or saline. In experiment 1, animals were tested on an operant delayed non-match to position task (working memory). Experiment 2 used a standard fixed-platform location water maze task (long-term memory), while experiment 3 used a variable-platform location water maze task (long-term memory and working memory). Amphetamine-sensitized animals were not impaired on any of these tasks. In experiment 4, animals were assessed on a strategy selection task in which they were first required to learn to locate a food reward using a particular learning strategy (place or response) then to learn to shift to an alternate learning strategy (response or place). Amphetamine-sensitized animals were not impaired on this task. In the final experiment animals were found to be impaired in performance of the extra-dimensional shift component of an attentional set-shifting task. These results suggest that while amphetamine sensitization does not produce memory impairments similar to those seen in schizophrenia, it does produce strong impairments in set-shifting, suggesting changes in prefrontal function similar to those seen in schizophrenia.

Involvement of the medial septum in stress-induced relapse to heroin seeking in rats.

Intermittent footshock stress has been shown to reinstate extinguished drug‐taking behaviour in rats, but the brain areas involved in this effect are to a large degree unknown. Here we studied the role of the septum in stress‐induced reinstatement of heroin seeking. Rats were trained to self‐administer heroin for 9–10 days (three 3‐h sessions per day, 0.1 mg/kg per infusion). Following training, extinction sessions were given for 8–13 days by substituting saline for heroin, and then tests for reinstatement of heroin seeking were carried out. Reversible inactivation of the medial septum with tetrodotoxin (TTX; 1–5 ng, infused 25–40 min before the test sessions) reliably reinstated heroin seeking, mimicking the effect of 15 min of intermittent footshock. This effect of TTX was not observed after infusions made 1.5 mm dorsally into the lateral septum. In other experiments, it was found that infusions of a low, subthreshold dose of TTX (0.5 ng) into the medial septum, when combined with 2 min of footshock that in itself was ineffective, reinstated heroin seeking. Furthermore, electrical stimulation (400 μA pulses, 100 μs duration, 100 Hz frequency) of the medial septum during exposure to 10 min of intermittent footshock attenuated footshock‐induced reinstatement of heroin seeking. These data suggest a role for the medial septum in stress‐induced relapse to drug seeking. The septum is thought to be involved in neuronal processes underlying behavioural inhibition, thus we speculate that stressors provoke relapse by interfering with these processes.

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

BACKGROUND Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.

Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice.

Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.

Chronic exposure to a gambling-like schedule of reward predictive stimuli can promote sensitization to amphetamine in rats

Addiction is considered to be a brain disease caused by chronic exposure to drugs. Sensitization of brain dopamine (DA) systems partly mediates this effect. Pathological gambling (PG) is considered to be a behavioral addiction. Therefore, PG may be caused by chronic exposure to gambling. Identifying a gambling-induced sensitization of DA systems would support this possibility. Gambling rewards evoke DA release. One episode of slot machine play shifts the DA response from reward delivery to onset of cues (spinning reels) for reward, in line with temporal difference learning principles. Thus, conditioned stimuli (CS) play a key role in DA responses to gambling. In primates, DA response to a CS is strongest when reward probability is 50%. Under this schedule the CS elicits an expectancy of reward but provides no information about whether it will occur on a given trial. During gambling, a 50% schedule should elicit maximal DA release. This closely matches reward frequency (46%) on a commercial slot machine. DA release can contribute to sensitization, especially for amphetamine. Chronic exposure to a CS that predicts reward 50% of the time could mimic this effect. We tested this hypothesis in three studies with rats. Animals received 15 × 45-min exposures to a CS that predicted reward with a probability of 0, 25, 50, 75, or 100%. The CS was a light; the reward was a 10% sucrose solution. After training, rats received a sensitizing regimen of five separate doses (1 mg/kg) of d-amphetamine. Lastly they received a 0.5 or 1 mg/kg amphetamine challenge prior to a 90-min locomotor activity test. In all three studies the 50% group displayed greater activity than the other groups in response to both challenge doses. Effect sizes were modest but consistent, as reflected by a significant group × rank association (ϕ = 0.986, p = 0.025). Chronic exposure to a gambling-like schedule of reward predictive stimuli can promote sensitization to amphetamine much like exposure to amphetamine itself.

Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population

Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia.