Selective tuning of hippocampal oscillations by phasic locus coeruleus activation in awake male rats.

Theta and gamma oscillations are thought to provide signal sets that promote neural coding of cognitive processes. Over 40 yrs ago, Jeffrey Gray reported event-related changes in a narrow band of hippocampal theta (7.5-8.5 Hz) which appeared to involve norepinephrine (NE) release from, the noradrenergic nucleus, the locus coeruleus (LC). These event-related alterations in EEG were elicited by novelty, attentional changes, the use of preparatory signals, and signal-mismatch events. Gray et al. have since provided indirect evidence that supports the role of NE in the modulation of 7.5- to 8.5-Hz oscillations in the hippocampus, but studies investigating the effects of direct LC activation in awake rats have been lacking. In the present study, dentate gyrus EEG was examined during glutamatergic activation of the LC in awake male rats in relation to plasticity effects on simultaneously recorded perforant path-evoked field potentials. Glutamate-injected animals were divided into three groups based on histological and plasticity outcomes; perforant path stimulated controls were also included. The three injected groups were: (1) rats with positive LC placements, demonstrating NE-LTP of the dentate gyrus evoked potential, (2) rats with positive LC placements, without NE-LTP, and (3) Non-LC injected controls. Activation of the LC in awake rats demonstrating NE-LTP increased the relative power of 7- to 9-Hz theta, a result masked in broader 4- to 12-Hz analysis. Comparatively, urethane-anesthetized rats showed an increase in 5-7 Hz, but not 7- to 9-Hz theta with LC activation. Discriminative analysis in the approximate theta band predicted by Gray (7.4-8.5 Hz) revealed that awake rats demonstrating NE-LTP had increased relative power in this narrow frequency compared to rats receiving perforant path only (noninjected) and Non-LC injected rats. Transiently reduced gamma (20-40 Hz) relative power was most commonly observed in rats with verified LC placements failing to express NE-LTP. Given current theories of LC function, these results suggest oscillatory tuning within the theta and gamma range may facilitate shifts in cognitive set.

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice.

Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.

The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP). Importantly, NF1 causes learning disabilities and attention deficits. A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1+/-) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP), a cellular mechanism of learning and memory. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity in the brain. Lovastatin is a specific inhibitor of three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used commonly for the treatment of hypercholesterolemia. We report that lovastatin decreased the enhanced brain p21Ras-MAPK activity of the nf1+/- mice, rescued their LTP deficits, and reversed their spatial learning and attention impairments. Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1.

Locus ceruleus activation suppresses feedforward interneurons and reduces beta-gamma electroencephalogram frequencies while it enhances theta frequencies in rat dentate gyrus.

The locus ceruleus is activated by novel stimuli, and its activation promotes learning and memory. Phasic activation of locus ceruleus neurons by glutamate enhances the dentate gyrus population spike amplitude and results in long-term potentiation of synaptic responses recorded after 24 h. Cholinergic activation of locus ceruleus neurons increases hippocampal . At the level of the cellular network, it is not clear how the potentiating effects of norepinephrine are mediated. Previous studies show that exogenous norepinephrine enhances inhibitory interneuron firing in the dentate gyrus. This finding appears at odds with evidence for potentiation. In this study, natural release of norepinephrine was induced by glutamate activation of locus ceruleus while we recorded EEGs and physiologically identified interneurons in the dentate gyrus of urethane-anesthetized rats. Feedforward neurons were inhibited (approximately 1-2 min) by locus ceruleus activation. Feedback interneurons showed both increased and decreased activity, whereas granule cells increased firing as predicted by evoked potential studies. EEG results replicated an increase in power (4-8 Hz) with locus ceruleus activation, but the effect with glutamatergic locus ceruleus activation was transient (approximately 1-2 min). Beta-gamma Frequencies were also transiently suppressed. Together, the data suggest that locus ceruleus activation enhances the throughput of concomitant sensory input by reducing feedforward inhibitory interneuron activity, which may reduce "binding" in existing cell assemblies, and enhances the conditions for synaptic plasticity through disinhibition, promotion of 4-8 Hz , and noradrenergic potentiation to facilitate the building of new representations.

New circuits for old memories: the role of the neocortex in consolidation.

Studies of learning and memory have provided a great deal of evidence implicating hippocampal mechanisms in the initial storage of facts and events. However, until recently, there were few hints as to how and where this information was permanently stored. A recent series of rodent molecular and cellular cognition studies provide compelling evidence for the involvement of specific neocortical regions in the storage of information initially processed in the hippocampus. Areas of the prefrontal cortex, including the anterior cingulate and prelimbic cortices, and the temporal cortex show robust increases in activity specifically following remote memory retrieval. Importantly, damage to or inactivation of these areas produces selective remote memory deficits. Additionally, transgenic studies provide glimpses into the molecular and cellular mechanisms underlying cortical memory consolidation. The studies reviewed here represent the first exciting steps toward the understanding of the molecular, cellular, and systems mechanisms of how the brain stores our oldest and perhaps most defining memories.