Long-range synchrony between medial prefrontal cortex, thalamus and hippocampus underlies working memory behavior in mice.

Presently, there are no antipsychotic drugs capable of treating the cognitive dysfunctions of schizophrenia. In order to inform the development of better therapies, it is essential to understand the mechanism behind dysfunctional cognition, which requires an understanding of functional cognition. Spatial working memory, a measure of cognitive function, can be assessed in the mouse using a task of delayed alternation: the T-maze. In this thesis, I focus on spatial working memory behavior in the mouse and three brain regions that are implicated in this behavior: the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the medial dorsal thalamus (MD). Lesion and electrophysiological studies in each structure have demonstrated their importance during working memory behavior. Disconnection studies also show that the coordination between the mPFC and either the HPC or MD is important for the behavior, but little is known about the mechanism by which they coordinate. The MD and the ventral region of the hippocampus (vHPC) have robust projections into the mPFC. They are therefore in a good position to influence mPFC activity. Previous reports show that the mPFC and the dorsal region of the hippocampus (dHPC) synchronize activity in the theta range (4-12 Hz) with working memory demand. However, the dHPC does not directly connect with the mPFC so it is unclear how this coordination occurs. We hypothesized that the vHPC may also be involved in spatial working memory behavior and that it may mediate the dHPC-mPFC theta synchrony observed. To test these hypotheses, we recorded neural activity simultaneously from the mPFC, dHPC and vHPC in mice performing the T-maze task. Local field potential oscillations (LFPs), thought to be a measure of synchronized synaptic activity, were obtained from each area. We observed an increase in theta synchrony between the mPFC and both the dHPC and vHPC. Removing the influence of vHPC both analytically and experimentally, we found a decrease in synchrony of the dHPC-mPFC.Aside from the disconnection studies, little is known about the MD-mPFC pathway in rodents. However, due to evidence from schizophrenia patients of altered correlation specifically between the MD and PFC, we hypothesized that an electrophysiological correlate of working memory exists in the MD-mPFC pathway as well and that a decrease in MD activity may lead to prefrontal dysfunction. To test these hypotheses, we recorded LFPs from the mPFC and both single unit activity and LFPs from the MD in mice performing the T-maze task. We observed an increase in phase locking of MD cells to mPFC LFPs in beta (13-30Hz) range during the choice phase of the task. We then utilized a pharmacogenetic technique to decrease firing rate in a small portion of MD cells, which resulted in a deficit in both task acquisition and performance. The increase in MD-mPFC beta phase locking we had observed was not present in MD-inactivated animals. Interestingly, beta coherence between the two structures across learning was highly correlated with choice accuracy on the task. This suggests that MD-PFC coordination is predictive of working memory performance.These findings illustrate how long-range synchrony of the mPFC with HPC in the theta frequency range and with the MD in the beta frequency range may be important markers for normal working memory behavior and if disrupted in humans, could contribute to the cognitive symptoms of schizophrenia

Inhibition of Mediodorsal Thalamus Disrupts Thalamofrontal Connectivity and Cognition

Cognitive deficits are central to schizophrenia but the underlying mechanisms still remain unclear. Imaging studies performed in patients point to decreased activity in the medio-dorsal thalamus (MD) and reduced functional connectivity between the MD and prefrontal cortex (PFC) as candidate mechanisms. However, a causal link is still missing. We used a pharmacogenetic approach in mice to diminish MD neuron activity and examined the behavioral and physiological consequences. We found that a subtle decrease in MD activity is sufficient to trigger selective impairments in prefrontal-dependent cognitive tasks. In vivo recordings in behaving animals revealed that MD-PFC beta-range synchrony is enhanced during acquisition and performance of a working memory task. Decreasing MD activity interfered with this task-dependent modulation of MD-PFC synchrony, which correlated with impaired working memory. These findings suggest that altered MD activity is sufficient to disrupt prefrontal-dependent cognitive behaviors, and could contribute to the cognitive symptoms observed in schizophrenia

Retrieval and Reconsolidation Accounts of Fear Extinction.

Extinction is the primary mode for the treatment of anxiety disorders. However, extinction memories are prone to relapse. For example, fear is likely to return when a prolonged time period intervenes between extinction and a subsequent encounter with the fear-provoking stimulus (spontaneous recovery). Therefore there is considerable interest in the development of procedures that strengthen extinction and to prevent such recovery of fear. We contrasted two procedures in rats that have been reported to cause such deepened extinction. One where extinction begins before the initial consolidation of fear memory begins (immediate extinction) and another where extinction begins after a brief exposure to the consolidated fear stimulus. The latter is thought to open a period of memory vulnerability similar to that which occurs during initial consolidation (reconsolidation update). We also included a standard extinction treatment and a control procedure that reversed the brief exposure and extinction phases. Spontaneous recovery was only found with the standard extinction treatment. In a separate experiment we tested fear shortly after extinction (i.e., within 6 h). All extinction procedures, except reconsolidation update reduced fear at this short-term test. The findings suggest that strengthened extinction can result from alteration in both retrieval and consolidation processes

The BaBar detector: Upgrades, operation and performance

Contains fulltext : 121729.pdf (preprint version ) (Open Access

Observation of CP violation in the B0 meson system

We present an updated measurement of time-dependent CP-violating asymmetries in neutral B decays with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. This result uses an additional sample of Upsilon(4S) decays collected in 2001, bringing the data available to 32 million B-anti-B pairs. We select events in which one neutral B meson is fully reconstructed in a final state containing charmonium and the flavor of the other neutral B meson is determined from its decay products. The amplitude of the CP-violating asymmetry, which in the Standard Model is proportional to sin2beta, is derived from the decay time distributions in such events. The result sin2beta = 0.59 +/- 0.14 (stat) +/- 0.05 (syst) establishes CP violation in the B^0 meson system. We also determine |lambda| = 0.93 +/- 0.09 {stat} +/- 0.03 {syst}, consistent with no direct CP violation.Comment: 8 pages, 2 figures, submitted to Physical Review Letter

Measurement of CP-violating asymmetries in B° decays to CP Eigenstates

We present measurements of time-dependent CP-violating asymmetries in neutral B decays to several CP eigenstates. The measurement uses a data sample of 23x10(6) Upsilon(4S)-->BbarB decays collected by the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we find events in which one neutral B meson is fully reconstructed in a CP eigenstate containing charmonium and the flavor of the other neutral B meson is determined from its decay products. The amplitude of the CP-violating asymmetry, which in the standard model is proportional to sin2beta, is derived from the decay time distributions in such events. The result is sin2beta = 0.34+/-0.20 (stat)+/-0.05 (syst)

The BaBar detector

Contains fulltext : 128916.pdf (publisher's version ) (Closed access