A Defined Network of Fast-Spiking Interneurons in Orbitofrontal Cortex: Responses to Behavioral Contingencies and Ketamine Administration

Orbitofrontal cortex (OFC) is a region of prefrontal cortex implicated in the motivational control of behavior and in related abnormalities seen in psychosis and depression. It has been hypothesized that a critical mechanism in these disorders is the dysfunction of GABAergic interneurons that normally regulate prefrontal information processing. Here, we studied a subclass of interneurons isolated in rat OFC using extracellular waveform and spike train analysis. During performance of a goal-directed behavioral task, the firing of this class of putative fast-spiking (FS) interneurons showed robust temporal correlations indicative of a functionally coherent network. FS cell activity also co-varied with behavioral response latency, a key indicator of motivational state. Systemic administration of ketamine, a drug that can mimic psychosis, preferentially inhibited this cell class. Together, these results support the idea that OFC–FS interneurons form a critical link in the regulation of motivation by prefrontal circuits during normal and abnormal brain and behavioral states

Evaluation of the Oscillatory Interference Model of Grid Cell Firing through Analysis and Measured Period Variance of Some Biological Oscillators

Models of the hexagonally arrayed spatial activity pattern of grid cell firing in the literature generally fall into two main categories: continuous attractor models or oscillatory interference models. Burak and Fiete (2009, PLoS Comput Biol) recently examined noise in two continuous attractor models, but did not consider oscillatory interference models in detail. Here we analyze an oscillatory interference model to examine the effects of noise on its stability and spatial firing properties. We show analytically that the square of the drift in encoded position due to noise is proportional to time and inversely proportional to the number of oscillators. We also show there is a relatively fixed breakdown point, independent of many parameters of the model, past which noise overwhelms the spatial signal. Based on this result, we show that a pair of oscillators are expected to maintain a stable grid for approximately t = 5µ3/(4πσ)2 seconds where µ is the mean period of an oscillator in seconds and σ2 its variance in seconds2. We apply this criterion to recordings of individual persistent spiking neurons in postsubiculum (dorsal presubiculum) and layers III and V of entorhinal cortex, to subthreshold membrane potential oscillation recordings in layer II stellate cells of medial entorhinal cortex and to values from the literature regarding medial septum theta bursting cells. All oscillators examined have expected stability times far below those seen in experimental recordings of grid cells, suggesting the examined biological oscillators are unfit as a substrate for current implementations of oscillatory interference models. However, oscillatory interference models can tolerate small amounts of noise, suggesting the utility of circuit level effects which might reduce oscillator variability. Further implications for grid cell models are discussed

Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics

<p>Abstract</p> <p>Background</p> <p>One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology.</p> <p>Methods</p> <p>We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (<it>CFH</it>) on chromosome 1q25 and variants in the <it>ARMS2</it>/HtrA serine peptidase 1 (<it>HTRA1</it>) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data.</p> <p>Results</p> <p>In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of <it>ARMS2</it>/<it>HTRA1 </it>rs1049331.</p> <p>Conclusions</p> <p>These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified.</p

The association between diet quality, dietary patterns and depression in adults: a systematic review

BACKGROUND: Recent evidence suggests that diet modifies key biological factors associated with the development of depression; however, associations between diet quality and depression are not fully understood. We performed a systematic review to evaluate existing evidence regarding the association between diet quality and depression. METHOD: A computer-aided literature search was conducted using Medline, CINAHL, and PsycINFO, January 1965 to October 2011, and a best-evidence analysis performed. RESULTS: Twenty-five studies from nine countries met eligibility criteria. Our best-evidence analyses found limited evidence to support an association between traditional diets (Mediterranean or Norwegian diets) and depression. We also observed a conflicting level of evidence for associations between (i) a traditional Japanese diet and depression, (ii) a “healthy” diet and depression, (iii) a Western diet and depression, and (iv) individuals with depression and the likelihood of eating a less healthy diet. CONCLUSION: To our knowledge, this is the first review to synthesize and critically analyze evidence regarding diet quality, dietary patterns and depression. Further studies are urgently required to elucidate whether a true causal association exists

Neural mechanisms involved in memory formation and retrieval within the rodent hippocampus : an in vivo electrophysiological study

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2002.Includes bibliographical references.While it is well established that the rodent hippocampus plays a crucial role in the formation and retrieval of spatial memories, the neural mechanisms underlying this process have not been completely characterized. In this thesis I have combined large-scale recordings from multiple single cells within the hippocampus of behaving rodents with pharmacological and genetic manipulations of hippocampal function in order to investigate how the cellular and network properties of the hippocampus contribute to memory storage and retrieval. In Part I of this thesis, extracellular recordings are used to monitor systematic changes in the cellular properties of hippocampal pyramidal cells in vivo. These studies demonstrate that the biophysical characteristics of CA1 pyramidal cells undergo both short term (activity-dependent) and long-term (experience-dependent) modulations during behavior. Short tem changes in the biophysical state of hippocampal pyramidal cells interact with changes in synaptic input to determine the probability with which CA1 pyramidal cells generate single spikes or bursts of action potentials and may play an important role in influencing where and when mechanisms of plasticity are engaged during behavior (Chapters: 3-4). Longer term changes include: 1) input specific reductions in amplitude attenuation - consistent with an increase in dendritic excitability (Chapter 4), 2) increases in the rate of spike repolarization (Chapter 5), 3) reductions in spike count variability within bursts (Chapter 5), and modulations in burst length both during behavior and sleep (Chapter5).(cont.) Together, these results provide novel insights into how changes in the intrinsic properties of hippocampal pyramidal cells are related to the process of memory formation. In Part II of this thesis, hippocampal recordings are used to characterize a novel genetically engineered mouse line in which NMDA receptors are specifically deleted from pyramidal cells within the CA3 region of the adult hippocampus (CA3-NR1 KO; Nakazawa et.al., 2001). Results indicate that while spatial information is relatively preserved within the hippocampus of CA3-NR1 mice, CA1 place cell activity within mutant animals is more sensitive to perturbations of the sensory environment relative to place cell activity in control animals. Together with behavioral data, these results provide the first direct evidence for CA3 NMDA receptor involvement in associative memory recall.by Michael C. Quirk.Ph.D