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Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice (Jonathan Epp)

AUTHORS: M. L. Mustroph, J. R. Merritt, A. L. Holloway, H. Pinardo, D. S. Miller, C. N. Kilby, P. Bucko, A. Wyer and J. S. Rhodes

ABSTRACT: Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity  and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin–thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without  running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided  neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine  (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar  in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons  (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice

showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the  same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal  neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.


Natural neural projection dynamics underlying social behavior (Sungmo Park)

AUTHORS: Lisa A. Gunaydin, Logan Grosenick, Joel C. Finkelstein, Isaac V. Kauvar, Lief E. Fenno, Avishek Adhikari, Stephan Lammel, Julie J. Mirzabekov, Raag D. Airan, Kelly A. Zalocusky, Kay M. Tye, Polina Anikeeva, Robert C. Malenka, and Karl Deisseroth

ABSTRACT: Social interaction is a complex behavior essential for many species, and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically- and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social but not novel-object interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection as sufficient to modulate social behavior, which was mediated by type-1 dopamine receptor signaling downstream in the NAc. Direct observation of projection-specific activity in this way captures a fundamental and previously inaccessible dimension of circuit dynamics.

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Parental olfactory experience influences behavior and neural structure in subsequent generations (Jana Husse)

AUTHORS: Brian G Dias & Kerry J Ressler

ABSTRACT: Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.

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Amygdala-Dependent Fear Memory Consolidation via miR-34a and Notch Signaling (Valentina Mercaldo)

AUTHORS: Brian George Dias, Jared Vega Goodman, Ranbir Ahluwalia, Audrey Elizabeth Easton, Raul Andero, and Kerry James Ressler

ABSTRACT: Using an array-based approach after auditory fear conditioning and microRNA (miRNA) sponge-mediated inhibition, we identified a role for miR-34a within the basolateral amygdala (BLA) in fear memory consolidation. Luciferase assays and bioinformatics suggested the Notch pathway as a target of miR-34a. mRNA and protein levels of Notch receptors and ligands are downregulated in a time- and learning-specific manner after fear conditioning in the amygdala. Systemic and stereotaxic manipulations of the Notch pathway indicated that Notch signaling in the BLA suppresses fear memory consolidation. Impairment of fear memory consolidation after inhibition of miR-34a within the BLA is rescued by inhibiting Notch signaling. Together, these data suggest that within the BLA, a transient decrease in Notch signaling, via miR-34a regulation, is important for the consolidation of fear memory. This work expands the idea that developmental molecules have roles in adult behavior and that existing interventions targeting them hold promise for treating neuropsychiatric disorders.



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Long-Range Connectivity Defines Behavioral Specificity of Amygdala Neurons (Adelaide Yiu)

AUTHORS: Verena Senn, Steffen B.E. Wolff, Cyril Herry, Francois Grenier, Ingrid Ehrlich,Jan Grundemann, Jonathan P. Fadok, Christian Muller, Johannes J. Letzkus, and Andreas Luthi

ABSTRACT: Memories are acquired and encoded within largescale neuronal networks spanning different brain areas. The anatomical and functional specificity of such long-range interactions and their role in learning is poorly understood. The amygdala and the medial prefrontal cortex (mPFC) are interconnected brain structures involved in the extinction of conditioned fear. Here, we show that a defined subpopulation of basal amygdala (BA) projection neurons targeting the prelimbic (PL) subdivision of mPFC is active during states of high fear, whereas BA neurons targeting the infralimbic (IL) subdivision are recruited, and exhibit cell-type-specific plasticity, during fear extinction. Pathway-specific optogenetic manipulations demonstrate that the activity balance between pathways is causally involved in fear extinction. Together, our findings demonstrate that, although intermingled locally, long-range connectivity defines distinct subpopulations of amygdala projection neurons and indicate that the formation of long-term extinction memories depends on the balance of activity between two defined amygdala-prefrontal pathways.

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Coordination of entorhinal–hippocampal ensemble activity during associative learning (Gisella Vetere)

AUTHORS: Kei M. Igarashi, Li Lu, Laura L. Colgin, May-Britt Moser & Edvard I. Moser

ABSTRACT: Accumulating evidence points to cortical oscillations as a mechanism for mediating interactions among functionally specialized neurons in distributed brain circuits1–6. A brain function that may use such interactions is declarative memory—that is, memory that can be consciously recalled, such as episodes and facts. Declarative memory is enabled by circuits in the entorhinal cortex that interface the hippocampus with the neocortex7,8. During encoding and retrieval of declarative memories, entorhinal and hippocampal circuits are thought to interact via theta and gamma oscillations4,6,8, which in awake rodents predominate frequency spectra in both regions9–12. In favour of this idea, theta–gamma coupling has been observed between entorhinal cortex and hippocampus under steady-state conditions inwell-trained rats12;however, the relationship between inter regional coupling and memory formation remains poorly understood. Here we show, by multisite recording at successive stages of associative learning, that the coherence of firing patterns in directly connected entorhinal–hippocampus circuits evolves as rats learn to use an odour cue to guide navigational behaviour, and that such coherence is invariably linked to the development of ensemble representations for unique trial outcomes in each area. Entorhinal–hippocampal coupling was observed specifically in the 20–40-hertz frequency band and specifically between the distal part of hippocampal area CA1 and the lateral part of entorhinal cortex, the subfields that receive the predominant olfactory input to the hippocampal region13. Collectively, the results identify 20–40-hertz oscillations as a mechanism for synchronizing evolving representations in dispersed neural circuits during encoding and retrieval of olfactory–spatial associative memory.

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Engineering a memory with LTD and LTP (Axel Guskjolen)

AUTHORS: Sadegh Nabavi, Rocky Fox, Christophe D. Proulx, John Y. Lin, Roger Y. Tsien & Roberto Malinow

ABSTRACT: It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD)1. However, the causal link between these synaptic processes and memory has been difficult to demonstrate2. Here we show that fear conditioning3–8, a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. We began by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning3–8. Subsequent optogenetic delivery of LTDconditioning to the auditory input inactivatesmemory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, we have engineered inactivation and reactivation of a memory using LTD and LTP, supporting a causal link between these synaptic processes and memory.

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Independent hypothalamic circuits for social and predator fear (Sungmo Park)

AUTHORS: Bianca A Silva, Camilla Mattucci, Piotr Krzywkowski, Emanuele Murana, Anna Illarionova, Valery Grinevich, Newton S Canteras, Davide Ragozzino & Cornelius T Gross

ABSTRACT: The neural circuits mediating fear to naturalistic threats are poorly understood. We found that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region that has been implicated in feeding, sex and aggression, are essential for predator and social fear in mice. Our results establish a critical role for VMH in fear and have implications
for selective intervention in pathological fear in humans.

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Parvalbumin interneurons mediate neuronal circuitry–neurogenesis coupling in the adult hippocampus (Yosuke Niibori)

AUTHORS: Juan Song, Jiaqi Sun, Jonathan Moss, Zhexing Wen, Gerald J Sun, Derek Hsu, Chun Zhong, Heydar Davoudi, Kimberly M Christian, Nicolas Toni, Guo-li Ming & Hongjun Song

ABSTRACT: Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local circuit activity to the diametric regulation of two critical early phases of adult hippocampal neurogenesis.

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Contrasting forms of cocaine-evoked plasticity control components of relapse (Liz Hsiang)

AUTHORS: Vincent Pascoli, Jean Terrier, Julie Espallergues, Emmanuel Valjent, Eoin Cornelius O’Connor & Christian Luscher

ABSTRACT: Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cueassociated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-D-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking,whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.