We previously reported involvement of right prefrontal cholinergic activity in veridical signal detection. Here, we first recorded real-time acetylcholine release in prefrontal cortex during specific trial sequences in rats performing a task requiring signal detection as well as rejection of non-signal events. Cholinergic release events recorded with sub-second resolution (“transients”) were observed only during signal-hit trials, not during signal-miss trials or non-signal events. Moreover, cholinergic transients were not observed for consecutive hits; instead they were limited to signal-hit trials that were preceded by factual or perceived non-signal events (“incongruent hits”). This finding suggests that these transients mediate shifts from a state of perceptual attention, or monitoring for cues, to cue-evoked activation of response rules and the generation of a cue-directed response. Next, to determine the translational significance of the cognitive operations supporting incongruent hits we employed a version of the task previously validated for use in research in humans and BOLD-fMRI. Incongruent hits activated a region in the right rostral prefrontal cortex (BA 10). Furthermore, greater prefrontal activation was correlated with faster response times for incongruent hits. Finally, we measured tissue oxygen in rats, as a proxy for BOLD, and found prefrontal increases in oxygen levels solely during incongruent hits. These cross-species studies link a cholinergic response to a prefrontal BOLD activation and indicate that these interrelated mechanisms mediate the integration of external cues with internal representations to initiate and guide behavior.

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Summary:To try to identify the critical structures during epileptogenesis, we used the lithium-pilocarpine model that reproduces most clinical and neuropathological features of temporal lobe epilepsy (TLE). We used imaging techniques as well as a disease modifying approach and pharmacological strategy. With [ 14 C]-2-deoxyglucose autoradiography, we assessed changes in cerebral glucose utilization. T 2 -weighted magnetic resonance imaging (MRI, 4.7 T) allowed follow-up of structures involved in epileptogenesis. A potential disease-modifying effect was studied using preconditioning with brief seizures (amygdala kindling, maximal electroshocks) and pharmacological strategies including vigabatrin (250 mg/kg), caffeine (0.3 g/L in drinking water), topiramate (10-60 mg/kg), pregabalin (50 mg/kg followed by 10 mg/kg), or RWJ-333369 (10-120 mg/kg). In adult and PN21 rats that became epileptic, entorhinal, and piriform cortices were the initial structures exhibiting significant signal changes on MRI scans, from 6 h after status epilepticus (SE) onset, reflecting neuronal death. In PN21 rats that did not become epileptic, no signal occurred in parahippocampal cortices. In hippocampus, MRI signal change appeared 36-48 h after SE, and progressively worsened to sclerosis. During the latent and chronic phases, the metabolic level in the hilus of adult and PN21 epileptic rats was normal although neuronal loss reached 60-75%. Protection limited to CA1 and/or CA3 (caffeine, topiramate, vigabatrin, amygdala kindling) did not affect the latency to spontaneous seizures. Protection limited to the entorhinal and piriform cortices (pregabalin) delayed epileptogenesis. The combined protection of Ammon's horn and parahippocampal cortices (RWJ-333369) prolonged the latency before the onset of seizures in a dose-dependent manner or, in some cases, prevented the epilepsy. The entorhinal and piriform cortices are critically involved in the early phase of the epileptogenesis while the hilus may initiate and/or maintain epileptic seizures. Pharmacological protection of the basal cortices is necessary for a beneficial disease-modifying effect but this must be combined with protection of the hippocampus to prevent epileptogenesis in this model of TLE.

Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABAA receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-1-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.