Faculty Bibliography

Whereas hippocampal activity is thought to be driven by precise conjunctions of sensory input, a recent study by Villette and Malvache et al. (Villette et al., 2015, in this issue of Neuron) reveals that neurons imaged in a static sensory environment organize into sequences endowed with intrinsic spatiotemporal properties.

The rodent piriform cortex (PCX) is a paleocortical structure known to support olfactory perception toward learned behavior. While the anterior PCX is used in associative odor object information decoding, the posterior PCX receives more descending input fibers from brain structures such as the amygdala that are thought to provide a qualitative relevance to raw odor percepts. Here we investigate the influence of top-down influence of specific brain regions on spontaneous and odor-induced activity in the posterior PCX at the single unit level. Using optogenetic techniques, we artificially stimulated descending fibers in the posterior PCX that were virally transduced from one of two interconnected brain regions. Specifically, the lateral and basolateral amygdala (LA/BLA) and the lateral entorhinal cortex (LEC) were independently targeted to express Channelrhodopsin in pyramidal neurons that also express CaMKII. Photostimulation at 473nm and 1mW near infected axon terminals in the posterior piriform was sufficient to drive temporally coincident responses of unit activity and local field potential, as recorded in anaesthetized animals injected at any one of the two target regions. Odorpaired photostimulation of descending fibers at the posterior PCX modulated local single unit response patterns compared to odor only. Photo-induced effects on unit odor responses ranged from suppressive to stimulatory, which often varied depending on the combinatorial timing of odor and light stimulation. These results demonstrate the importance of top-down inputs to piriform cortex in odor coding, and highlight that cortical odor processing takes place in a rich milieu of sensory, emotional and contextual information

As is true in all sensory systems, chemosensory perception reflects not only the external stimulus, but also the internal state and past experiences of the perceiver. This means that perception of stable stimulus input may be highly variable as the perceiver's state (e.g., hunger/satiety, fearful/secure, etc.) and experience with the stimulus (e.g., novel/familiar, expected/unexpected) changes. That is, the same basic sensory circuit may produce different outputs depending on internal state and past experience. These changes in sensory coding and circuit function appear to derive from changes in both neuromodulatory tone and from feedback from higher order, non-sensory circuits. While these processes occur in all sensory systems, they may be particularly relevant in the chemical senses which monitor stimuli relevant to nutrition, reproduction, kin recognition and predator avoidance. This symposium will present new data from both the olfactory (Kay, Mandairon, Sadrian) and gustatory (Fontanini) systems exploring how this internal modulation occurs. The talks will include diverse research techniques primarily in awake animals (e.g., single-unit recordings, local field potential recordings, pharmacological and optogenetic manipulations, novel behavioral assays) which examine the role of neuromodulatory systems as well as inputs to primary sensory regions providing feedback information regarding expectation, memory and hedonics. TEST

Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca(2+) levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca(2+)-levels to RA synthesis remains unknown. Here we identify the Ca(2+)-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARalpha. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca(2+)-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

A fundamental question in olfaction is how individual olfactory receptors contribute to odor perception. The Trace Amine- Associated Receptors (TAARs) are a small set of evolutionarily conserved main olfactory receptors that respond preferentially to amines and that contribute significantly to amine perception. We are using a combination of gene targeting, electrophysiology, in vivo imaging, and behavior to dissect the contribution of individual TAARs to amine sensitivity. Odorant detection thresholds were measured in mice lacking specific TAAR genes using a go-no go behavioral assay. Genetic deletion of all olfactory TAARs causes a 10-fold decrease in sensitivity to isopentylamine and a 50-fold decrease in sensitivity to phenylethylamine. This indicates that TAARs play a significant role in determining behavioral sensitivity to amines. Our electrophysiological and in vivo imaging experiments indicate that the TAARs are broadly tuned to amines. Phenylethylamine preferentially activates TAAR4, and isopentylamine activates both TAAR4 and TAAR3, with TAAR3 being slightly more sensitive. Genetic deletion of TAAR4 by itself elicits a 10-fold decrease in sensitivity to phenylethylamine, indicating that TAAR4 is the most sensitive receptor for this odorant. Behavioral threshold for isopenylamine is not affected by TAAR4 deletion, indicating that isopentylamine sensitivity may be set by TAAR3, or may be set by either TAAR3 or TAAR4. Our results indicate that single olfactory receptors can contribute significantly to odor detection, and that the TAARs are most likely the most sensitive amine receptors. More generally, our approach allows us to characterize for the first time in mammals how chemical detection at the molecular level relates to olfactory performance at the behavioral level

Episodic memory decline, olfactory identification deficits and the ApoE-e4 allele constitute risk factors for incident Alzheimers' Disease (AD). However, the relationships among these three risk factors are poorly understood, in part due to the paucity of large longitudinal datasets that involve such assessments. The present study used data from the Betula study (n=1225), which involves memory testing every five years. Participants completed an odor identification test, were genotyped for the ApoE gene, and had completed episodic memory testing for a 10-year period (3 testing occasions) leading up to the olfactory assessment. The episodic memory measure was a composite of five tasks, and decline was defined as an estimated change >1SD below the age norm. Participants were thus classified as "decliners" (n=125) or "non-decliners" (n=1100). Results showed that decliners had a poorer olfactory identification than nondecliners. However, when ApoE-e4 was taken into consideration, the association between memory decline and odor identification deficit was only present in ApoE-e4 carriers, whereas odor identification in memory decliners without e4 reached the same level as that of non-decliners. Future research on the role of olfaction in age-related memory impairment and dementia should consider the mediating role played by the ApoE-e4

We reconstructed the synaptic circuits of seven columns in the second neuropil or medulla behind the fly's compound eye. These neurons embody some of the most stereotyped circuits in one of the most miniaturized of animal brains. The reconstructions allow us, for the first time to our knowledge, to study variations between circuits in the medulla's neighboring columns. This variation in the number of synapses and the types of their synaptic partners has previously been little addressed because methods that visualize multiple circuits have not resolved detailed connections, and existing connectomic studies, which can see such connections, have not so far examined multiple reconstructions of the same circuit. Here, we address the omission by comparing the circuits common to all seven columns to assess variation in their connection strengths and the resultant rates of several different and distinct types of connection error. Error rates reveal that, overall, <1% of contacts are not part of a consensus circuit, and we classify those contacts that supplement (E+) or are missing from it (E-). Autapses, in which the same cell is both presynaptic and postsynaptic at the same synapse, are occasionally seen; two cells in particular, Dm9 and Mi1, form >/=20-fold more autapses than do other neurons. These results delimit the accuracy of developmental events that establish and normally maintain synaptic circuits with such precision, and thereby address the operation of such circuits. They also establish a precedent for error rates that will be required in the new science of connectomics.

Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC-hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories.

Sensory-motor reflex circuits are the basic units from which animal nervous systems are constructed, yet little is known regarding how connections within these simple networks are established. In papers in Cell Reports and in this issue of Neuron, Zheng et al. (2015a, 2015b) demonstrate that coordinate activities of Hox genes in sensory neurons and interneurons govern connectivity within touch-reflex circuits in C. elegans.