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Functional connectivity-based parcellation and connectome of cortical midline structures in the mouse: a perfusion autoradiography study (Leo Restivo)

AUTHORS: Daniel P. Holschneider, Zhuo Wang and Raina D. Pang

ABSTRACT: Rodent cortical midline structures (CMS) are involved in emotional, cognitive and attentional processes. Tract tracing has revealed complex patterns of structural connectivity demonstrating connectivity-based integration and segregation for the prelimbic, cingulate area 1, retrosplenial dysgranular cortices dorsally, and infralimbic, cingulate area 2, and retrosplenial granular cortices ventrally. Understanding of CMS functional connectivity (FC) remains more limited. Here we present the first subregion-level FC analysis of the mouse CMS, and assess whether fear results in state-dependent FC changes analogous to what has been reported in humans. Brain mapping using [14C]-iodoantipyrine was performed in mice during auditory-cued fear conditioned recall and in controls. Regional cerebral blood flow (CBF) was analyzed in 3-D images reconstructed from brain autoradiographs. Regions-of-interest were selected along the CMS anterior-posterior and dorsal-ventral axes. In controls, pairwise correlation and graph theoretical analyses showed strong FC within each CMS structure, strong FC along the dorsal-ventral axis, with segregation of anterior from posterior structures. Seed correlation showed FC of anterior regions to limbic/paralimbic areas, and FC of posterior regions to sensory areas–findings consistent with functional segregation noted in humans. Fear recall increased FC between the cingulate and retrosplenial cortices, but decreased FC between dorsal and ventral structures. In agreement with reports in humans, fear recall broadened FC of anterior structures to the amygdala and to somatosensory areas, suggesting integration and processing of both limbic and sensory information. Organizational principles learned from animal models at the mesoscopic level (brain regions and pathways) will not only critically inform future work at the microscopic (single neurons and synapses) level, but also have translational value to advance our understanding of human brain architecture.

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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.

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The Hippocampus Plays a Selective Role in the Retrieval of Detailed Contextual Memories (Aijing Gao)

AUTHORS: Brian J. Wiltgen, Miou Zhou, Ying Cai, J. Balaji, Mikael Guzman Karlsson, Sherveen N. Parivash, Weidong Li, and Alcino J. Silva

ABSTRACT: Background: It is widely believed that the hippocampus plays a temporary role in the retrieval of episodic and contextual memories. Initial research indicated that damage to this structure produced amnesia for newly acquired memories but did not affect those formed in the distant past. A number of recent studies, however, have found that the hippocampus is required for the retrieval of episodic and contextual memories regardless of their age. These findings are currently the subject of intense debate, and a satisfying resolution has yet to be identified.

Results: The current experiments address this issue by demonstrating that detailed memories require the hippocampus, whereas memories that lose precision become independent of this structure. First, we show that the dorsal hippocampus is preferentially activated by the retrieval of detailed contextual fear memories. We then establish that the hippocampus is necessary for the retrieval of detailed memories by using a context-generalization procedure. Mice that exhibit high levels of generalization to a novel environment show no memory loss when the hippocampus is subsequently inactivated. In contrast, mice that discriminate between contexts are significantly impaired by hippocampus inactivation.

Conclusions: Our data suggest that detailed contextual memories require the hippocampus, whereas memories that lose precision can be retrieved without this structure. These findings can account for discrepancies in the literature—memories of our distant past can be either lost or retained after hippocampus damage depending on their quality—and provide a new framework for understanding memory consolidation.

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Synaptic encoding of fear extinction in mPFC-amygdala circuits (Dekel Taliaz)

AUTHORS: Cho JHDeisseroth KBolshakov VY.

ABSTRACT: Retrieval of fear extinction memory is associated with increased firing of neurons in the medial prefrontal cortex (mPFC). It is unknown, however, how extinction learning-induced changes in mPFC activity are relayed to target structures in the amygdala, resulting in diminished fear responses. Here, we show that fear extinction decreases the efficacy of excitatory synaptic transmission in projections from the mPFC to the basolateral nucleus of the amygdala (BLA), whereas inhibitory responses are not altered. In contrast, synaptic strength at direct mPFC inputs to intercalated neurons remains unchanged after extinction. Moreover, priming stimulation of mPFC projections induced heterosynaptic inhibition in auditory cortical inputs to the BLA. These synaptic mechanisms could contribute to the encoding of extinction memory by diminishing the ability of projections from the mPFC to drive BLA activity while retaining the ability of intercalated neurons to inhibit the output nuclei of the amygdala.

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Hippocampal Activity Patterns Carry Information about Objects in Temporal Context (Matt Tran)

AUTHORS: Liang-Tien Hsieh, Matthias J. Gruber, Lucas J. Jenkins,and Charan Ranganath

ABSTRACT: The hippocampus is critical for human episodic memory, but its role remains controversial. One fundamental question concerns whether the hippocampus represents specific objects or assigns context-dependent representations to objects. Here, we used multivoxel pattern similarity analysis of fMRI data during retrieval of learned object sequences to systematically investigate hippocampal coding of object and temporal context information.Hippocampal activity patterns carried information about the temporal positions of objects in learned sequences, but not about objects or temporal positions in random sequences. Hippocampal activity patterns differentiated between overlapping object sequences and between temporally adjacent objects that belonged to distinct sequence contexts. Parahippocampal and perirhinal cortex showed different pattern information profiles consistent with coding of temporal position and object information, respectively. These findings are consistent with models proposing that the hippocampus represents objects within specific temporal contexts, a capability that might explain its critical role in episodic memory.

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Functional Connectivity between Amygdala and Cingulate Cortex for Adaptive Aversive Learning (Chen Yan)

AUTHORS: Oded Klavir, Rotem Genud-Gabai, and Rony Paz

ABSTRACT: The ability to switch flexibly between aversive and neutral behaviors based on predictive cues relies on learning driven by surprise or errors in outcome prediction. Surprise can occur as absolute value of the error (unsigned error) or its direction (signed errors; positive when something unexpected is delivered and negative when something expected is omitted). Signed and unsigned errors coexist in the brain and were associated with different systems, but how they interact and form across large networks remains vague. We recorded simultaneously in the amygdala and dorsal anterior cingulate cortex (dACC) of monkeys performing a reversal aversive-conditioning paradigm and quantified changes in interregional correlations when contingencies shift. We report that errors exist in different magnitudes and that they differentially develop at millisecond resolution. Our results support a model where unsigned errors first develop in the amygdala during successful learning and then propagate into the dACC, where signed errors develop and are distributed back to the amygdala.