The Parahippocampal Cortex and its Functional Connection with the Hippocampus are Critical for Nonnavigational Spatial Memory in Macaques.

The Hamilton Search Task (HST) is a test of nonnavigational spatial memory that is dependent on the hippocampus. The parahippocampal cortex (PHC) is a major route for spatial information to reach the hippocampus, but the extent to which the PHC and hippocampus function independently of one another in the context of nonnavigational spatial memory is unclear. Here, we tested the hypotheses that (1) bilateral pharmacological inactivation of the PHC would impair HST performance, and (2) that functional disconnection of the PHC and hippocampus by contralateral (crossed) inactivation would likewise impair performance. Transient inactivation of the PHC impaired HST performance most robustly with 30 s intertrial delays, but not when color cues were introduced. Functional disconnection of the PHC and hippocampus, but not separate unilateral inactivation of either region, also selectively impaired long-term spatial memory. These findings indicate a critical role for the PHC and its interactions with the hippocampus in nonnavigational spatial memory.

Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.

A large body of literature links risk of cognitive decline, mild cognitive impairment (MCI) and dementia with Type 2 Diabetes (T2D) or pre-diabetes. Accumulating evidence implicates a close relationship between the brain insulin receptor signaling pathway (IRSP) and the accumulation of amyloid beta and hyperphosphorylated and conformationally abnormal tau. We showed previously that the neuropathological features of Alzheimer's disease (AD were reduced in patients with diabetes who were treated with insulin and oral antidiabetic medications. To understand better the neurobiological substrates of T2D and T2D medications in AD, we examined IRSP and endothelial cell markers in the parahippocampal gyrus of controls (N = 30), of persons with AD (N = 19), and of persons with AD and T2D, who, in turn, had been treated with anti-diabetic drugs (insulin and or oral agents; N = 34). We studied the gene expression of selected members of the IRSP and selective endothelial cell markers in bulk postmortem tissue from the parahippocampal gyrus and in endothelial cell enriched isolates from the same brain region. The results indicated that there are considerable abnormalities and reductions in gene expression (bulk tissue homogenates and endothelial cell isolates) in the parahippocampal gyri of persons with AD that map directly to genes associated with the microvasculature and the IRSP. Our results also showed that the numbers of abnormally expressed microvasculature and IRSP associated genes in diabetic AD donors who had been treated with anti-diabetic agents were reduced significantly. These findings suggest that anti-diabetic treatments may reduce or normalize compromised microvascular and IRSP functions in AD.

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

Importance: Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear. Objective: To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis. Design, Setting, and Participants: In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication-naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied. Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017. Interventions: A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo. Control participants were not given any drug. All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task. Main Outcomes and Measures: Brain activation during verbal encoding and recall, indexed using the blood oxygen level-dependent hemodynamic response fMRI signal. Results: Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 22.43 (4.95) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 25.35 (5.24) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 23.89 (4.14) years. Brain activation (indexed using the median sum of squares ratio of the blood oxygen level-dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group. Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, -0.027; interquartile range [IQR], -0.041 to -0.016; control: median, 0.020; IQR, -0.022 to 0.056; P < .001) and in the parahippocampal gyrus and midbrain during recall (placebo: median, 0.002; IQR, -0.016 to 0.010; control: median, 0.035; IQR, 0.015 to 0.039; P < .001). Within these 3 regions, activation in the CBD group was greater than in the placebo group but lower than in the control group (parahippocampal gyrus/midbrain: CBD: median, -0.013; IQR, -0.027 to 0.002; placebo: median, -0.007; IQR, -0.019 to 0.008; control: median, 0.034; IQR, 0.005 to 0.059); the level of activation in the CBD group was thus intermediate to that in the other 2 groups. There were no significant group differences in task performance. Conclusions and Relevance: Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state. As these regions are critical to the pathophysiology of psychosis, the influence of CBD at these sites could underlie its therapeutic effects on psychotic symptoms. Trial Registration: isrctn.org Identifier: ISRCTN46322781.

Neural Underpinnings of Cortisol Effects on Fear Extinction.

Extinction of conditioned fear embodies a crucial mechanism incorporated in exposure therapy. Clinical studies demonstrated that application of the stress hormone cortisol before exposure sessions facilitates exposure success, but the underlying neural correlates remain unknown. Context- and stimulus-dependent cortisol effects on extinction learning will be characterized in this study and tested in the extinction and in a new context. Forty healthy men participated in a 3-day fear conditioning experiment with fear acquisition in context A (day 1), extinction training in context B (day 2), and recall in context B and a new context C one week later (day 3). Hydrocortisone (30 mg) or placebo was given before extinction training. Blood-oxygen-level-dependent responses and skin conductance responses (SCRs) served as dependent measures. At the beginning of extinction training, cortisol reduced conditioned SCRs, diminished activation of the amygdala-hippocampal complex, and enhanced functional connectivity of the anterior parahippocampal gyrus with the ventromedial prefrontal cortex (vmPFC). After one week, the cortisol group showed increased hippocampal activation and connectivity to the vmPFC toward an extinguished stimulus and reduced insula activation toward a nonextinguished stimulus in the extinction context. However, this inhibitory cortisol effect did not extend to the new context. Taken together, cortisol reduced fear recall at the beginning of extinction and facilitated the consolidation of the extinction memory as evidenced by an inhibitory activation pattern one week later. The stress hormone exerted a critical impact on the amygdala-hippocampus-vmPFC network underlying fear and extinction memories. However, cortisol did not attenuate the context dependency of extinction.

Hippocampal gamma-slow oscillation coupling in macaques during sedation and sleep.

Behavioral and neurophysiological evidence suggests that the slow (≤1 Hz) oscillation (SO) during sleep plays a role in consolidating hippocampal (HIPP)-dependent memories. The effects of the SO on HIPP activity have been studied in rodents and cats both during natural sleep and during anesthetic administration titrated to mimic sleep-like slow rhythms. In this study, we sought to document these effects in primates. First, HIPP field potentials were recorded during ketamine-dexmedetomidine sedation and during natural sleep in three rhesus macaques. Sedation produced regionally-specific slow and gamma (∼40 Hz) oscillations with strong coupling between the SO phase and gamma amplitude. These same features were seen in slow-wave sleep (SWS), but the coupling was weaker and the coupled gamma oscillation had a higher frequency (∼70 Hz) during SWS. Second, electrical stimuli were delivered to HIPP afferents in the parahippocampal gyrus (PHG) during sedation to assess the effects of sleep-like SO on excitability. Gamma bursts after the peak of SO cycles corresponded to periods of increased gain of monosynaptic connections between the PHG and HIPP. However, the two PHG-HIPP connectivity gains during sedation were both substantially lower than when the animal was awake. We conclude that the SO is correlated with rhythmic excitation and inhibition of the PHG-HIPP network, modulating connectivity and gamma generators intrinsic to this network. Ketamine-dexmedetomidine sedation produces a similar effect, but with a decreased contribution of the PHG to HIPP activity and gamma generation.

LSD modulates music-induced imagery via changes in parahippocampal connectivity.

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC-visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context.

Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations.

RATIONALE: During the last years, considerable progress has been made toward understanding the neuronal basis of consciousness by using sophisticated behavioral tasks, brain-imaging techniques, and various psychoactive drugs. Nevertheless, the neuronal mechanisms underlying some of the most intriguing states of consciousness, including spiritual experiences, remain unknown. OBJECTIVES: To elucidate state of consciousness-related neuronal mechanisms, human subjects were given psilocybin, a naturally occurring serotonergic agonist and hallucinogen that has been used for centuries to induce spiritual experiences in religious and medical rituals. METHODS: In this double-blind, placebo-controlled study, 50 healthy human volunteers received a moderate dose of psilocybin, while high-density electroencephalogram (EEG) recordings were taken during eyes-open and eyes-closed resting states. The current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions were computed and correlated with psilocybin-induced altered states of consciousness. RESULTS: Psilocybin decreased the current source density of neuronal oscillations at 1.5-20 Hz within a neural network comprising the anterior and posterior cingulate cortices and the parahippocampal regions. Most intriguingly, the intensity levels of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of delta oscillations (1.5-4 Hz) between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area. CONCLUSIONS: These results provide systematic evidence for the direct association of a specific spatiotemporal neuronal mechanism with spiritual experiences and enhanced insight into life and existence. The identified mechanism may constitute a pathway for modulating mental health, as spiritual experiences can promote sustained well-being and psychological resilience.

Distinct binding of amyloid imaging ligands to unique amyloid-ß deposited in the presubiculum of Alzheimer's disease.

Non-invasive determination of amyloid-ß peptide (Aß) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aß for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aß deposits lacking interaction with the commonly used amyloid dyes FSB. (11)C-PiB, (3)H-AZD2184, and (125)I-DRK092 showed overt binding to presubicular Aß deposits, while (125)I-DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aß lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aß aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aß deposits. Amyloid radioligands lacking affinity for this component, such as (125)I-DRM106, may selectively capture Aß deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aß pathologies. Non-invasive determination of amyloid-ß peptide (Aß) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for radioligand binding in these two regions could serve for developing novel imaging agents selectively visualizing neurotoxicity-related Aß pathologies.

Acute effects of alcohol on the human brain: a resting-state FMRI study.

The aim of this study is to assess the value of resting-state fMRI in detecting the acute effects of alcohol on healthy human brains. Thirty-two healthy volunteers were studied by conventional MR imaging and resting-state fMRI prior to and 0.5 hours after initiation of acute alcohol administration. The fMRI data, acquired during the resting state, were correlated with different breath alcohol concentrations (BrAC). We use the posterior cingulate cortex/precuneus as a seed for the default mode network (DMN) analysis. ALFF and ReHo were also used to investigate spontaneous neural activity in the resting state. Conventional MR imaging showed no abnormalities on all subjects. Compared with the prior alcohol administration, the ALFF and ReHo also indicated some specific brain regions which are affected by alcohol, including the superior frontal gyrus, cerebellum, hippocampal gyrus, left basal ganglia, and right internal capsule. Functional connectivity of the DMN was affected by alcohol. This resting-state fMRI indicates that brain regions implicated are affected by alcohol and might provide a neural basis for alcohol's effects on behavioral performance.

Gating of hippocampal output by ß-adrenergic receptor activation in the pilocarpine model of epilepsy.

Norepinephrine acting via ß-adrenergic receptors (ß-ARs) plays an important role in hippocampal plasticity including the subiculum which is the principal target of CA1 pyramidal cells and which controls information transfer from the hippocampus to other brain regions including the neighboring presubiculum and the entorhinal cortex (EC). Subicular pyramidal cells are classified as regular- (RS) and burst-spiking (BS) cells. Activation of ß-ARs at CA1-subiculum synapses induces long-term potentiation (LTP) in burst- but not in RS cells (Wójtowicz et al., 2010). To elucidate seizure-associated disturbances in the norepinephrine-dependent modulation of hippocampal output, we investigated the functional consequences of the ß-AR-dependent synaptic plasticity at CA1-subiculum synapses for the transfer of hippocampal output to the parahippocampal region in the pilocarpine model of temporal lobe epilepsy. Using single-cell and multi-channel field recordings in slices, we studied ß-AR-mediated changes in the functional connectivity between CA1, the subiculum and its target-structures. We confirm that application of the ß-adrenergic agonist isoproterenol induces LTP in subicular BS- but not RS cells. Due to the distinct spatial distribution of RS- and BS cells in the proximo-to-distal axis of the subiculum, in field recordings, LTP was significantly stronger in the distal than in the proximal subiculum. In pilocarpine-treated animals, ß-AR-mediated LTP was strongly reduced in the distal subiculum. The attenuated LTP was associated with a disturbed polysynaptic transmission from the CA1, via the subiculum to the presubiculum, but with a preserved transmission to the medial EC. Our findings suggest that synaptic plasticity may influence target-related information flow and that such regulation is disturbed in pilocarpine-treated epileptic rats.

Differences in regional cerebral blood flow response to a 5HT3 antagonist in early- and late-onset cocaine-dependent subjects.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients.

Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers.

BACKGROUND: Cannabis can induce transient psychotic symptoms, but not all users experience these adverse effects. We compared the neural response to Δ9-tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms. Method In a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task. RESULTS: The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic (TP; n = 11) and non-psychotic (NP; n = 10) groups. During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal gyri and in the right cerebellum. In these regions, THC had opposite effects on activation relative to placebo in the two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum, independent of the effects of THC. CONCLUSIONS: In this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC, we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the effects of the drug on psychotic symptoms.

[Disorders of neurogenesis of cortical and subcortical structures in rat brain limbic system during fetal alcohol syndrome formation].

Disorders of neurogenesis of cortical and subcortical structures in rat brain limbic system were studied in the offspring of rats that received ethanol during pregnancy. The methods used included the staining of histological sections with cresyl violet, in vitro culture, and electron paramagnetic resonance. Prenatal alcohol intoxication was shown to induce the disturbances in proliferative activity of granular layer cells in the hippocampal dentate gyrus, neuron- and glioblast migration, enhancement of free NO and lipoperoxide production and cell death. This resulted in the changes in the number of neurons in cortical and subcortical structures of rat brain limbic system and in fetal alcohol syndrome formation.

Hippocampal novelty activations in schizophrenia: disease and medication effects.

We examined hippocampal activation in schizophrenia (SZ) with fMRI BOLD in response to the presentation of novel and familiar scenes. Voxel-wise analysis showed no group differences. However, anatomical region-of-interest analyses contrasting normal (NL), SZ-on-medication (SZ-ON), SZ-off-medication (SZ-OFF) showed substantial differences in MTL-based novelty responding, accounted for by the reduction in novelty responses in the SZ-OFF predominantly in the anterior hippocampus and parahippocampal cortex. These differences in novelty-based activation in the SZ-OFF group represent disease characteristics of schizophrenia without confounding effects of antipsychotic medication and illustrate the tendency of antipsychotic drug treatment to improve memory functions in schizophrenia.

Somatostatin and neuropeptide Y neurons undergo different plasticity in parahippocampal regions in kainic acid-induced epilepsy.

Parahippocampal brain areas including the subiculum, presubiculum and parasubiculum, and entorhinal cortex give rise to major input and output neurons of the hippocampus and exert increased excitability in animal models and human temporal lobe epilepsy. Using immunohistochemistry and in situ hybridization for somatostatin and neuropeptide Y, we investigated plastic morphologic and neurochemical changes in parahippocampal neurons in the kainic acid (KA) model of temporal lobe epilepsy. Although constitutively contained in similar subclasses of γ-aminobutyric acid (GABA)-ergic neurons, both neuropeptide systems undergo distinctly different changes in their expression. Somatostatin messenger RNA (mRNA) is rapidly but transiently expressed de novo in pyramidal neurons of the subiculum and entorhinal cortex 24 hours after KA. Surviving somatostatin interneurons display increased mRNA levels at late intervals (3 months) after KA and increased labeling of their terminals in the outer molecular layer of the subiculum; the labeling correlates with the number of spontaneous seizures, suggesting that the seizures may trigger somatostatin expression. In contrast, neuropeptide Y mRNA is consistently expressed in principal neurons of the proximal subiculum and the lateral entorhinal cortex and labeling for the peptide persistently increased in virtually all major excitatory pathways of the hippocampal formation. The pronounced plastic changes differentially involving both neuropeptide systems indicate marked rearrangement of parahippocampal areas, presumably aiming at endogenous seizure protection. Their receptors may be targets for anticonvulsive drug therapy.

Treatment course with antidepressant therapy in late-life depression.

OBJECTIVE: In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial. METHOD: In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time. RESULTS: Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyper-intensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not. CONCLUSIONS: These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.

Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice.

Stressful life events and chronic stress are implicated in the development of depressive disorder in humans. Neuropeptide Y (NPY) and galanin have been shown to modulate the stress response, and exert antidepressant-like effects in rodents. To further investigate these neuropeptides in depression-like behaviour, NPY and galanin gene expression was studied in brains of mice subjected to chronic restraint stress (CRS) and concomitant treatment with the antidepressant fluoxetine (FLX). CRS caused a significant increase in depression-like behaviour that was associated with increased NPY mRNA levels in the medial amygdala. Concomitant FLX treatment reverted depression-like effects of CRS and led to significant increases in levels of NPY and galanin mRNA in the dentate gyrus, amygdala, and piriform cortex. These findings suggest that effects on NPY and galanin gene expression could play a role in the antidepressant effects of FLX.

Perirhinal cortex hyperexcitability in pilocarpine-treated epileptic rats.

The perirhinal cortex (PC), which is heavily connected with several epileptogenic regions of the limbic system such as the entorhinal cortex and amygdala, is involved in the generation and spread of seizures. However, the functional alterations occurring within an epileptic PC network are unknown. Here, we analyzed this issue by using in vitro electrophysiology and immunohistochemistry in brain tissue obtained from pilocarpine-treated epileptic rats and age-matched, nonepileptic controls (NECs). Neurons recorded intracellularly from the PC deep layers in the two experimental groups had similar intrinsic and firing properties and generated spontaneous depolarizing and hyperpolarizing postsynaptic potentials with comparable duration and amplitude. However, spontaneous and stimulus-induced epileptiform discharges were seen with field potential recordings in over one-fifth of pilocarpine-treated slices but never in NEC tissue. These network events were reduced in duration by antagonizing NMDA receptors and abolished by NMDA + non-NMDA glutamatergic receptor antagonists. Pharmacologically isolated isolated inhibitory postsynaptic potentials had reversal potentials for the early GABA(A) receptor-mediated component that were significantly more depolarized in pilocarpine-treated cells. Experiments with a potassium-chloride cotransporter 2 antibody identified, in pilocarpine-treated PC, a significant immunostaining decrease that could not be explained by neuronal loss. However, interneurons expressing parvalbumin and neuropeptide Y were found to be decreased throughout the PC, whereas cholecystokinin-positive cells were diminished in superficial layers. These findings demonstrate synaptic hyperexcitability that is contributed by attenuated inhibition in the PC of pilocarpine-treated epileptic rats and underscore the role of PC networks in temporal lobe epilepsy.

Scopolamine disrupts hippocampal activity during allocentric spatial memory in humans: an fMRI study using a virtual reality analogue of the Morris Water Maze.

The role of the septohippocampal cholinergic system in memory disorders is well established. The effects of cholinergic challenge in animals have been extensively studied using the Morris Water Maze (MWM) which engages allocentric spatial memory. The present study investigated the effect of the centrally active muscarinic antagonist scopolamine on allocentric spatial memory in humans using a virtual reality analogue of the MWM task, the Arena task. Twenty right-handed healthy male adults with a mean age of 28 years (range 23-35 years) were studied using functional MRI in a randomized double-blind cross-over design with scopolamine bromide (0.4 mg i.m.) or placebo (saline) administered 70-90 min before the beginning of the functional scan. Scopolamine induced a significant reduction in the activation of the hippocampus/parahippocampal gyrus compared with placebo. Furthermore, there was dissociation between hippocampus-based and striatal-based memory systems, which were significantly more activated in the placebo and scopolamine conditions, respectively. The activation of the striatal system under scopolamine challenge was accompanied by the activation of the amygdala. In conclusion, the study extends the well-documented finding in animals of the attenuating effect of scopolamine on hippocampal activity during allocentric spatial memory to humans. Furthermore, the results call for further investigation of the dissociation between the hippocampal and neostriatal memory systems during allocentric spatial processing under cholinergic blockade in humans.

In vitro ictogenesis and parahippocampal networks in a rodent model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is a chronic epileptic disorder involving the hippocampal formation. Details on the interactions between the hippocampus proper and parahippocampal networks during ictogenesis remain, however, unclear. In addition, recent findings have shown that epileptic limbic networks maintained in vitro are paradoxically less responsive than non-epileptic control (NEC) tissue to application of the convulsant drug 4-aminopyridine (4AP). Field potential recordings allowed us to establish here the effects of 4AP in brain slices obtained from NEC and pilocarpine-treated epileptic rats; these slices included the hippocampus and parahippocampal areas such as entorhinal and perirhinal cortices and the amygdala. First, we found that both types of tissue generate epileptiform discharges with similar electrographic characteristics. Further investigation showed that generation of robust ictal-like discharges in the epileptic rat tissue is (i) favored by decreased hippocampal output (ii) reinforced by EC-subiculum interactions and (iii) predominantly driven by amygdala networks. We propose that a functional switch to alternative synaptic routes may promote network hyperexcitability in the epileptic limbic system.