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Cocaine Place Conditioning Strengthens Location-Specific Hippocampal Coupling to the Nucleus Accumbens

Sjulson, Lucas; Peyrache, Adrien; Cumpelik, Andrea; Cassataro, Daniela; Buzsaki, Gyorgy
Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanisms are not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of D2-positive nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of coupling with hippocampal place cells that encode the cocaine-paired location. These findings provide in vivo evidence suggesting that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.
PMID: 29754750
ISSN: 1097-4199
CID: 3113492

Cell-Specific Targeting of Genetically Encoded Tools for Neuroscience

Sjulson, Lucas; Cassataro, Daniela; DasGupta, Shamik; Miesenbock, Gero
Genetically encoded tools for visualizing and manipulating neurons in vivo have led to significant advances in neuroscience, in large part because of the ability to target expression to specific cell populations of interest. Current methods enable targeting based on marker gene expression, development, anatomical projection pattern, synaptic connectivity, and recent activity as well as combinations of these factors. Here, we review these methods, focusing on issues of practical implementation as well as areas for future improvement. Expected final online publication date for the Annual Review of Genetics Volume 50 is November 23, 2016. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PMCID:5630135
PMID: 27732792
ISSN: 1545-2948
CID: 2278402

Novel Striatal GABAergic Interneuron Populations Labeled in the 5HT3aEGFP Mouse

Munoz-Manchado, A B; Foldi, C; Szydlowski, S; Sjulson, L; Farries, M; Wilson, C; Silberberg, G; Hjerling-Leffler, J
Histological and morphological studies indicate that approximately 5% of striatal neurons are cholinergic or gamma-aminobutyric acidergic (GABAergic) interneurons (gINs). However, the number of striatal neurons expressing known interneuron markers is too small to account for the entire interneuron population. We therefore studied the serotonin (5HT) receptor 3a-enhanced green fluorescent protein (5HT3a(EGFP)) mouse, in which we found that a large number of striatal gINs are labeled. Roughly 20% of 5HT3a(EGFP)-positive cells co-express parvalbumin and exhibit fast-spiking (FS) electrophysiological properties. However, the majority of labeled neurons do not overlap with known molecular interneuron markers. Intrinsic electrical properties reveal at least 2 distinct novel subtypes: a late-spiking (LS) neuropeptide-Y (NPY)-negative neurogliaform (NGF) interneuron, and a large heterogeneous population with several features resembling low-threshold-spiking (LTS) interneurons that do not express somatostatin, NPY, or neuronal nitric oxide synthase. Although the 5HT3a(EGFP) NGF and LTS-like interneurons have electrophysiological properties similar to previously described populations, they are pharmacologically distinct. In direct contrast to previously described NPY(+) LTS and NGF cells, LTS-like 5HT3a(EGFP) cells show robust responses to nicotine administration, while the 5HT3a(EGFP) NGF cell type shows little or no response. By constructing a molecular map of the overlap between these novel populations and existing interneuron populations, we are able to reconcile the morphological and molecular estimates of striatal interneuron numbers.
PMCID:4677971
PMID: 25146369
ISSN: 1460-2199
CID: 1878582

In vivo optogenetic identification and manipulation of GABAergic interneuron subtypes

Roux, Lisa; Stark, Eran; Sjulson, Lucas; Buzsaki, Gyorgy
Identification and manipulation of different GABAergic interneuron classes in the behaving animal are important to understand their role in circuit dynamics and behavior. The combination of optogenetics and large-scale neuronal recordings allows specific interneuron populations to be identified and perturbed for circuit analysis in intact animals. A crucial aspect of this approach is coupling electrophysiological recording with spatially and temporally precise light delivery. Focal multisite illumination of neuronal activators and silencers in predetermined temporal configurations or a closed loop manner opens the door to addressing many novel questions. Recent progress demonstrates the utility and power of this novel technique for interneuron research.
PMCID:4024355
PMID: 24440414
ISSN: 0959-4388
CID: 802042

Reverse Pharmacogenetic Modulation of the Nucleus Accumbens Reduces Ethanol Consumption in a Limited Access Paradigm

Cassataro, Daniela; Bergfeldt, Daniella; Malekian, Cariz; Van Snellenberg, Jared X; Thanos, Panayotis K; Fishell, Gord; Sjulson, Lucas
Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.Neuropsychopharmacology advance online publication, 23 October 2013; doi:10.1038/npp.2013.184.
PMCID:3870771
PMID: 23903031
ISSN: 0893-133x
CID: 622332

Psychiatric consequences of actual versus feared and perceived bed bug infestations: a case series examining a current epidemic

Rieder, Evan; Hamalian, Gareen; Maloy, Katherine; Streicker, Elizabeth; Sjulson, Lucas; Ying, Patrick
PMID: 22221725
ISSN: 1545-7206
CID: 149807

Writing memories with light-addressable reinforcement circuitry

Claridge-Chang, Adam; Roorda, Robert D; Vrontou, Eleftheria; Sjulson, Lucas; Li, Haiyan; Hirsh, Jay; Miesenbock, Gero
Dopaminergic neurons are thought to drive learning by signaling changes in the expectations of salient events, such as rewards or punishments. Olfactory conditioning in Drosophila requires direct dopamine action on intrinsic mushroom body neurons, the likely storage sites of olfactory memories. Neither the cellular sources of the conditioning dopamine nor its precise postsynaptic targets are known. By optically controlling genetically circumscribed subsets of dopaminergic neurons in the behaving fly, we have mapped the origin of aversive reinforcement signals to the PPL1 cluster of 12 dopaminergic cells. PPL1 projections target restricted domains in the vertical lobes and heel of the mushroom body. Artificially evoked activity in a small number of identifiable cells thus suffices for programming behaviorally meaningful memories. The delineation of core reinforcement circuitry is an essential first step in dissecting the neural mechanisms that compute and represent valuations, store associations, and guide actions.
PMCID:3920284
PMID: 19837039
ISSN: 0092-8674
CID: 394272

Rational optimization and imaging in vivo of a genetically encoded optical voltage reporter

Sjulson, Lucas; Miesenbock, Gero
The hybrid voltage sensor (hVOS) combines membrane-targeted green fluorescent protein and the hydrophobic anion dipicrylamine (DPA) to provide a promising tool for optical recording of electrical activity from genetically defined populations of neurons. However, large fluorescence signals are obtained only at high DPA concentrations (>3 mum) that increase membrane capacitance to a level that suppresses neural activity. Here, we develop a quantitative model of the sensor to guide its optimization and achieved an approximate threefold increase in fractional fluorescence change at a lower DPA concentration of 2 mum. Using this optimized voltage reporter, we perform optical recordings of evoked activity in the Drosophila antennal lobe with millisecond temporal resolution but fail to detect action potentials, presumably because spike initiation and/or propagation are inhibited by the capacitive load added even at reduced DPA membrane densities. We evaluate strategies for potential further improvement of hVOS quantitatively and derive theoretical performance limits for optical voltage reporters in general.
PMCID:2714581
PMID: 18495892
ISSN: 0270-6474
CID: 394282

Photocontrol of neural activity: biophysical mechanisms and performance in vivo

Sjulson, Lucas; Miesenbock, Gero
PMID: 18447399
ISSN: 0009-2665
CID: 394292

Excitatory local circuits and their implications for olfactory processing in the fly antennal lobe

Shang, Yuhua; Claridge-Chang, Adam; Sjulson, Lucas; Pypaert, Marc; Miesenbock, Gero
Conflicting views exist of how circuits of the antennal lobe, the insect equivalent of the olfactory bulb, translate input from olfactory receptor neurons (ORNs) into projection-neuron (PN) output. Synaptic connections between ORNs and PNs are one-to-one, yet PNs are more broadly tuned to odors than ORNs. The basis for this difference in receptive range remains unknown. Analyzing a Drosophila mutant lacking ORN input to one glomerulus, we show that some of the apparent complexity in the antennal lobe's output arises from lateral, interglomerular excitation of PNs. We describe a previously unidentified population of cholinergic local neurons (LNs) with multiglomerular processes. These excitatory LNs respond broadly to odors but exhibit little glomerular specificity in their synaptic output, suggesting that PNs are driven by a combination of glomerulus-specific ORN afferents and diffuse LN excitation. Lateral excitation may boost PN signals and enhance their transmission to third-order neurons in a mechanism akin to stochastic resonance.
PMCID:2866183
PMID: 17289577
ISSN: 0092-8674
CID: 394312