The New York State Psychiatric Institute

New York City, NY, United States

The New York State Psychiatric Institute

New York City, NY, United States
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Burghardt N.S.,Columbia University | Burghardt N.S.,The New York State Psychiatric Institute | Bauer E.P.,Barnard College
Neuroscience | Year: 2013

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30. years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-. d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy. © 2013 IBRO.


Adhikari A.,Columbia University | Topiwala M.A.,Columbia University | Gordon J.A.,Columbia University | Gordon J.A.,The New York State Psychiatric Institute
Neuron | Year: 2010

The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance. © 2010 Elsevier Inc. All rights reserved.


Burghardt N.S.,Columbia University | Burghardt N.S.,The New York State Psychiatric Institute | Park E.H.,New York University | Hen R.,Columbia University | And 2 more authors.
Hippocampus | Year: 2012

The hippocampus is involved in segregating memories, an ability that utilizes the neural process of pattern separation and allows for cognitive flexibility. We evaluated a proposed role for adult hippocampal neurogenesis in cognitive flexibility using variants of the active place avoidance task and two independent methods of ablating adult-born neurons, focal X-irradiation of the hippocampus, and genetic ablation of glial fibrillary acidic protein positive neural progenitor cells, in mice. We found that ablation of adult neurogenesis did not impair the ability to learn the initial location of a shock zone. However, when conflict was introduced by switching the location of the shock zone to the opposite side of the room, irradiated and transgenic mice entered the new shock zone location significantly more than their respective controls. This impairment was associated with increased upregulation of the immediate early gene Arc in the dorsal dentate gyrus, suggesting a role for adult neurogenesis in modulating network excitability and/or synaptic plasticity. Additional experiments revealed that irradiated mice were also impaired in learning to avoid a rotating shock zone when it was added to an initially learned stationary shock zone, but were unimpaired in learning the identical simultaneous task variant if it was their initial experience with place avoidance. Impaired avoidance could not be attributed to a deficit in extinction or an inability to learn a new shock zone location in a different environment. Together these results demonstrate that adult neurogenesis contributes to cognitive flexibility when it requires changing a learned response to a stimulus-evoked memory. © 2012 Wiley Periodicals, Inc.


Kheirbek M.A.,Columbia University | Kheirbek M.A.,The New York State Psychiatric Institute | Tannenholz L.,Columbia University | Tannenholz L.,The New York State Psychiatric Institute | And 2 more authors.
Journal of Neuroscience | Year: 2012

Adult-generated granule cells (GCs) in the dentate gyrus (DG) exhibit a period of heightened plasticity 4-6 weeks postmitosis. However, the functional contribution of this critical window of plasticity to hippocampal neurogenesis and behavior remains unknown. Here, we show that deletion of NR2B-containing NMDA receptors from adult-born GCs impairs a neurogenesis-dependent form of LTP in the DG and reduces dendritic complexity of adult-born GCs, but does not impact their survival. Mice in which the NR2B-containing NMDA receptor was deleted from adult-born GCs did not differ from controls in baseline anxiety-like behavior or discrimination of very different contexts, but were impaired in discrimination of highly similar contexts. These results indicate that NR2B-dependent plasticity of adult-born GCs is necessary for fine contextual discrimination and is consistent with their proposed role in pattern separation. ©2012 the authors.


Adhikari A.,Columbia University | Topiwala M.,Columbia University | Gordon J.,Columbia University | Gordon J.,The New York State Psychiatric Institute
Neuron | Year: 2011

The medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) functionally interact during innate anxiety tasks. To explore the consequences of this interaction, we examined task-related firing of single units from the mPFC of mice exploring standard and modified versions of the elevated plus maze (EPM), an innate anxiety paradigm. Hippocampal local field potentials (LFPs) were simultaneously monitored. The population of mPFC units distinguished between safe and aversive locations within the maze, regardless of the nature of the anxiogenic stimulus. Strikingly, mPFC units with stronger task-related activity were more strongly coupled to theta-frequency activity in the vHPC LFP. Lastly, task-related activity was inversely correlated with behavioral measures of anxiety. These results clarify the role of the vHPC-mPFC circuit in innate anxiety and underscore how specific inputs may be involved in the generation of behaviorally relevant neural activity within the mPFC. © 2011 Elsevier Inc.


Sahay A.,Columbia University | Sahay A.,The New York State Psychiatric Institute | Wilson D.,New York University | Hen R.,Columbia University | Hen R.,The New York State Psychiatric Institute
Neuron | Year: 2011

While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, " Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron. © 2011 Elsevier Inc.


Gordon J.A.,Columbia University | Gordon J.A.,The New York State Psychiatric Institute
Current Opinion in Neurobiology | Year: 2011

The hippocampus and medial prefrontal cortex subserve spatial working memory in rodents. Recent evidence has demonstrated functional interactions between these brain regions in the form of sychronization of oscillatory activity during behavior. The nature of this synchrony and its relationship to behavioral performance suggests an important role in the function of the hippocampal-prefrontal circuit. © 2011 Elsevier Ltd.


Wallace R.,The New York State Psychiatric Institute
BioSystems | Year: 2011

Tlusty's topological rate distortion analysis of the genetic code is applied to protein symmetries and protein folding rates. Unlike the genetic case, numerous thermodynamically accessible 'protein folding codes' can be identified from empirical classifications. Folding rates follow from a topologically driven rate distortion argument, a model that can, in principle, be extended to intrinsically disordered proteins. The elaborate cellular regulatory machinery of the endoplasmic reticulum and heat shock proteins is needed to prevent transition between the various thermodynamically 'natural' sets of hydrophobic-core protein conformations, and its corrosion by aging would account for the subsequent onset of many protein folding disorders. These results imply markedly different evolutionary trajectories for the genetic and protein folding codes, and suggest that the 'protein folding code' is really a complicated composite, distributed across protein production and a cellular, or higher, regulatory apparatus acting as a canalizing catalyst that drives the system to converge on particular transitive components within a significantly larger 'protein folding groupoid'. © 2010 Elsevier Ireland Ltd.


Wallace R.,The New York State Psychiatric Institute
Ecological Modelling | Year: 2016

Applying biological versions of the Data Rate Theorem and the Arrhenius reaction rate relation, it becomes clear that the search-and-response feedback of developmental selection associated with phenotypic plasticity requires a significant rate of metabolic free energy. Too rapid change in environmental conditions, often coupled with decline in available sources of metabolic free energy, leads to highly punctuated local extinction events. The observed dynamic is likely to be that the animal seems to adapt to environmental alterations for a long time, but then, and quite suddenly, developmental selection fails, leading to local extirpation of the reproducing population. Conversely, mosaicking, by imposing selection demands associated with diversity in time, space, and mode - as in traditional and conservation agricultures - can create energy barriers limiting the evolution and spread of pest or pathogen populations. © 2015 Elsevier B.V.


Wallace R.,The New York State Psychiatric Institute
BioSystems | Year: 2014

A recent line of study exploring statistical models of punctuated global broadcasts associated with attention states has focused on the evolutionary exaptation of the inevitable signal crosstalk between related sets of unconscious cognitive modules (UCM). This work invokes a groupoid treatment of the equivalence classes arising from information sources 'dual', in a formal sense, to the UCM, via a standard spontaneous symmetry breaking/lifting methodology abducted from statistical physics. A related approach involves an index theorem based on a stochastic empirical Onsager-like entropy-analog gradient model. Surprisingly, similar arguments may apply to 'fuzzy groupoid' generalizations likely to better fit biological complexities. © 2014 Elsevier Ireland Ltd.

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