Monthly Archives: May 2014

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Amygdala interneuron subtypes control fear learning through disinhibition (Asim Rashid)

AUTHORS: Steffen B. E. Wolff, Jan Grundemann, Philip Tovote, Sabine Krabbe, Gilad A. Jacobson, Christian Muller, Cyril Herry, Ingrid Ehrlich, Rainer W. Friedrich, Johannes J. Letzkus & Andreas Luthi

ABSTRACT: Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV1 interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM1 interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV1and SOM1 interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.

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Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression (Frances Xia)

AUTHORS: Julien Courtin, Fabrice Chaudun, Robert R. Rozeske, Nikolaos Karalis, Cecilia Gonzalez-Campo, Helene Wurtz, Azzedine Abdi, Jerome Baufreton, Thomas C. M. Bienvenu & Cyril Herry

ABSTRACT: Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses1–3. Incortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (c-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations4,5. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing6–8, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex9–12 (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories13–15. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.

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Structured Synaptic Connectivity between Hippocampal Regions (Valentina Mercaldo)

AUTHORS: Shaul Druckmann, Linqing Feng, Bokyoung Lee, Chaehyun Yook, Ting Zhao, Jeffrey C. Magee, Janelia Farm Research and Jinhyun Kim

ABSTRACT: The organization of synaptic connectivity within a neuronal circuit is a prime determinant of circuit function. We performed a comprehensive fine-scale circuit mapping of hippocampal regions (CA3-CA1) using the newly developed synapse labeling method, mGRASP. This mapping revealed spatially nonuniform and clustered synaptic connectivity patterns. Furthermore, synaptic clustering was enhanced between groups of neurons that shared a similar developmental/migration time window, suggesting a mechanism for establishing the spatial structure of synaptic connectivity. Such connectivity patterns are thought to effectively engage active dendritic processing and storage mechanisms, thereby potentially enhancing neuronal feature selectivity.

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Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice (Adam Santoro)

AUTHORS: Saul A Villeda, Kristopher E Plambeck, Jinte Middeldorp, Joseph M Castellano, Kira I Mosher, Jian Luo, Lucas K Smith, Gregor Bieri, Karin Lin, Daniela Berdnik, Rafael Wabl, Joe Udeochu, Elizabeth G Wheatley, Bende Zou, Danielle A Simmons, Xinmin S Xie, Frank M Longo & Tony Wyss-Coray

ABSTRACT: As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging1, 2. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts—in which circulatory systems of young and aged animals are connected—identified synaptic plasticity–related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

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Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease (Adelaide Yiu)

AUTHORS: Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff & Scott A Small

ABSTRACT: The entorhinal cortex has been implicated in the early stages of Alzheimer’s disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer’s disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.