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Contents lists available at SciVerse ScienceDirect

Behavioural Brain Research

j ourna l h om epage: www.elsev ier .com/ locate /bbr

eview

ptogenetic insights into striatal function and behavior

effrey D. Lenz, Mary Kay Lobo ∗

epartment of Anatomy and Neurobiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA

i g h l i g h t s

Optogenetics provides insight into distinct behavioral roles of striatal cell subtypes.Selective activation of the two striatal MSNs produces opposite behavioral responses.Modulating activity in striatal TANs alters rewarding behaviors and dopamine release.Modulating activity in striatal afferents influences reward and reinforcement.Temporal control of striatal signaling molecules alters reward.

a r t i c l e i n f o

rticle history:eceived 7 September 2012eceived in revised form 10 April 2013ccepted 15 April 2013vailable online xxx

eywords:ptogeneticstriatumotor Control

a b s t r a c t

Recent breakthroughs in optogenetic technologies to alter neuronal firing and function with light, com-bined with cell type-specific transgenic animal lines, has led to important insights into the function ofdistinct neuronal cell subtypes and afferent connections in the heterogeneously complex striatum. A vitalpart of the basal ganglia, the striatum is heavily implicated in both motor control and motivation-basedbehavior; as well as in neurological disorders and psychiatric diseases including Parkinson’s Disease,Huntington’s Disease, drug addiction, depression, and schizophrenia. Researchers are able to manipulatefiring and cell signaling with temporal precision using optogenetics in the two striatal medium spinyneuron (MSN) subpopulations, the striatal interneurons, and striatal afferents. These studies confirmedthe classical hypothesis of movement control and reward seeking behavior through direct versus indirect

ewardedium spiny neurons

onically active cholinergic interneurons

pathway MSNs; illuminated a selective role for TANs in cocaine reward; dissected the roles of glutamater-gic and dopaminergic inputs to striatum in reward; and highlighted a role for striatal signaling moleculesincluding an adrenergic G-protein coupled receptor in reward and the rho-GTPase Rac1 in cocaine rewardand cocaine induced structural plasticity. This review focuses on how the evolving optogenetic toolboxprovides insight into the distinct behavioral roles of striatal cell subpopulations and striatal afferents,which has clinically relevant implications into neurological disorders and psychiatric disease.

© 2013 Elsevier B.V. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Medium spiny neuron manipulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Striatal interneurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Striatal afferents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

5. Optogenetic tools to investigate molecular mechanisms of striatal behav6. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: Dstr, dorsal striatum; NAc, nucleus accumbens; MSN, medium spiny nTS, low threshold spiking interneuron; SN, substantia nigra; VTA, ventral tegmental area∗ Corresponding author. Tel.: +1 410 706 8824; fax: +1 410 706 2043.

E-mail address: mklobo@umaryland.edu (M.K. Lobo).

166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.bbr.2013.04.018

ights into striatal function and behavior. Behav Brain Res (2013),

iors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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euron; TAN, tonically active cholinergic interneuron; FS, fast spiking interneuron;.

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. Introduction

Within the last decade, optogenetics has made a profoundmpact on the field of neuroscience, allowing researchers to probeunctioning intact brain circuits in vivo. Optogenetics, a term coinedy Deisseroth and Boyden who have been instrumental in devel-ping this technology, involves two components: (1) the geneticargeting of opsin proteins, sensitive to specific wavelengths ofight, which can be targeted to specific neuronal populations; (2)he use of light to activate these proteins to modulate cellularunctions, including altering membrane potentials in a physiolog-cally relevant time course, as well as G-protein coupled signalingnd intracellular signaling with precise temporal precision [1–4]Fig. 1, Table 1). The most utilized optogenetic tools include theepolarizing channelrhodopsins (ChRs), light gated cation channelso activate neuronal firing and halorhopdopsin, a hyperpolarizingight driven chloride pump to silence neurons. The basal gangliaBG), specifically the striatum, is one system that researchers haveegun to explore behavioral functions using optogenetic tools.his review will detail the current findings in striatal function andehavior using optogenetics. More detailed accounts of the optoge-etic toolbox or utilization of optogenetics in other neural systemsan be found in several recently published reviews [3–5].

The striatum is broadly implicated in action selection includ-ng motor behavior, decision-making, and motivational processes6–10] and has been implicated in neurological disorders and neu-opsychiatric diseases such as Huntington’s Disease, Parkinson’sisease, schizophrenia, depression, and addiction [11,12]. Theseehaviors and brain diseases are mediated through different striatalegions, the dorsal striatum (dStr) predominantly mediates motorehaviors and decision making while the ventral striatum (a.k.a.ucleus accumbens; NAc) mediates motivational processes such aseward and hedonia [7–10].

Striatal neuronal subtypes are heterogeneously interspersedhroughout the striatum and characterized as described belowFig. 1). GABAergic medium spiny neurons (MSNs) compose 95%

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

f striatal neurons while the remaining 5% are interneurons.he interneurons include large tonically active cholinergic neu-ons (TANs) that receive glutamatergic inputs from cortex and

ig. 1. Expression of optogenetic proteins in striatal neuron subtypes. Examples of the opxpressed in a TAN interneuron, an OptoXR expressed in a D2+ MSN, LOV-Rac1 expressed inxpressed in all neurons in striatum, selective optogenetic expression and manipulation

PRESSn Research xxx (2013) xxx– xxx

thalamus, GABAergic inputs from MSNs, and dopaminergic inputsfrom the SN/VTA. TANs synapse primarily onto MSNs and otherTANs [7,13,14]. Another subclass of striatal interneurons are thefast spiking GABAergic (FS) interneurons that express parvalbuminand are similar to the FS interneurons found in the hippocampusand cortex. FS interneurons receive inhibitory inputs from otherinterneurons, inhibitory inputs from the globus pallidus, as well asexcitatory glutamatergic inputs from the thalamus and cortex, withtheir primary inhibitory synapses occurring on MSNs [12,15–19].A final distinct group of interneurons are the low threshold spiking(LTS) interneurons, which express somatostatin, neuropepetideY,and nitric oxide synthase [20–24]. LTS neurons are implicated inlong-term plasticity, receive glutamatergic inputs from the thala-mus and cortex, and synapse directly onto MSNs [16,24–26].

The MSNs are subdivided into two subtypes based on theiraxonal targets: striatonigral and striatopallidal MSNs. StriatonigralMSNs project to globus pallidus internal (GPi), ventral pallidum(VP) and midbrain regions including substantia nigra (SN) and ven-tral tegmental area (VTA) while striatopallidal MSNs project to theglobus pallidus external (GPe) and VP [27–30]. The two MSNs sub-types are further distinguished by their differential expression ofvarious genes; most notably G-protein coupled receptors and neu-ropeptides. Striatonigral MSNs express dopamine receptor 1 (D1),muscarinic receptor 4 (Chrm4), substance P, and dynorphin whilestriatopallidal MSNs express dopamine receptor 2 (D2), adeno-sine receptor 2a (Adora2a), G-protein coupled receptor 6 (Gpr6),and enkephalin [27,31–33]. These two MSN subtypes are heteroge-neously distributed in striosomes and matrix compartments in dStrand NAc. The patch vs. matrix compartments receive input from dif-ferent cortical regions, have differentiated outputs to the SN/VTA,and each region has specialized gene expression [27,34–36]. ThedStr is further subdivided into dorsal medial striatum (dmStr)and dorsal lateral striatum (dlStr), which have differential inputsand outputs [8,37–39]. The NAc is divided into core and shellregions, which also have distinct inputs from the cortex and differ-ent outputs to BG targets [40]. The projections from the striatum

ights into striatal function and behavior. Behav Brain Res (2013),

through BG output nuclei are classified into the direct and indirectpathways. The direct pathway, stemming from the striatonigralD1+ MSNs, is implicated in movement initiation, reinforcement,

togenetic proteins expressed in striatal neurons. They include ChR2 and eNpHR3.0 a D1+ MSN. Although many of these optogenetic proteins have been non-selectively

has not yet been used in the FS or LTS interneurons in the striatum.

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Table 1Optogenetic manipulation of striatal neurons.

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nd reward seeking. The indirect pathway, composed of the stri-topallidal D2+ MSNs, antagonizes the direct pathway by inhibitingovement, promoting punishment, and inhibiting reward seeking

34,41,42].Despite the known cytoarchitecture of the striatum, the het-

rogeneity of this structure has posed a major challenge indentification and manipulation of functional and molecular com-onents in specific striatal cell subtypes. This barrier was overcomeith the development of fluorescent reporter and Cre-recombinaseriver BAC transgenic lines within the last 15 years [27,28,43–48].any striatal cell subtype lines, including those expressing

uorescent reporters and Cre-recombinase in the two MSN sub-opulations and in striatal interneurons, have become vital tools inlucidating striatal function and behavior [32,49–54].

Many researchers have recently taken advantage of transgenicines expressing Channelrhodopsin 2 (ChR2) in striatal neurons orsed Cre-driver lines coupled with adeno associated viral (AAV)ouble inverted open reading frame (DIO) vectors to selectivelyxpress optically activated proteins in a specific brain region forptogenetic manipulation. A detailed protocol by Cardin et al. elo-

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

uently outlines exactly how to execute this experiment in virtuallyny brain region [55]. Furthermore, the first research article bysai, et al. to utilize the DIO-AAV-ChR2 vector in combination withyrosine hydroxylase (TH)-Cre BAC transgenic mice to selectively

.

express ChR2 in VTA dopamine neurons provides an exemplarymodel of optogenetic manipulation of specific cell types in vivoto examine neuronal correlates of behavioral encoding [56].

2. Medium spiny neuron manipulation

The two MSN subtypes through the direct vs. indirect pathwaysprovide opposing but balanced output through the BG circuit topromote normal function and behavior. This classical BG modelwas initially proposed to describe balanced movement and coor-dination through the motor pathways arising from these two MSNsubtypes and also provides a framework for the behavioral pathol-ogy, including unbalanced movement and coordination of motordisorders [41]. The BG model hypothesizes that activation of thedirect pathway facilitates movement while activation of the indi-rect pathway leads to movement inhibition [41,57,58]. With theadvances in optogenetics to alter cell firing or inhibit neurons, itwas recently possible to test this classical hypothesis of the func-tion of the direct and indirect pathways in striatal motor functionand motor disorders [50,59–61].

ights into striatal function and behavior. Behav Brain Res (2013),

Using the Cre recombinase dependent DIO-AAV-ChR2 virus toexpress ChR2 in each MSN subtype in D1-Cre or D2-Cre BAC trans-genic lines, Kravitz et al. were able to selectively activate dorsalstriatal direct or indirect pathways MSNs. Light activation of the

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1+ MSNs caused a significant increase in movement and reducedreezing in an open field, while activation of the D2+ MSNs resultedn increased freezing, bradykinesia and decreased motor initiations.sing 6-hydroxydopamine lesions as a model of Parkinson’s disease

he authors demonstrated that D1+ MSN activation rescued deficitsn freezing, bradykinesia and locomotor initiation [50]. These find-ngs demonstrated the ability to selectively activate distinct cellubtypes within the heterogeneous striatum and confirmed thathe direct and indirect BG pathways have opposing influences on

otor control. Furthermore, this study addressed a need to fullyharacterize the cell type specific contributions of BG pathways inotor disorders during the progression of the disease. Finally this

tudy highlights the relevance of alternative treatments, aimed atargeting specific neurons and/or circuits, in motor disorders.

The role of the direct vs. indirect pathway in motivation has beenoorly understood until recently. Most data implicated a directole for D1+ MSNs in drug or natural reward behavioral encod-ng as evidenced by induction of immediate early genes in D1+

SNs in response to drugs of abuse or natural reward [62–65].urthermore, overexpression of the FosB gene isoform, deltaFosB,n D1+ MSNs leads to enhanced drug and natural reward as wells resiliency to social defeat stress [66–70]. Ablating D2+ MSNs inAc enhanced amphetamine conditioned place preference, whichemonstrated a role for D2+ MSNs in inhibiting drug reward [60].ptogenetic studies have provided direct confirmation for the rolef MSN subtypes in motivation. Our group addressed the selectiveontribution of NAc D1+ and D2+ MSNs in reward seeking behav-ors. We selectively expressed ChR2 in D1+ or D2+ MSNs in theAc using D1-Cre and D2-Cre mouse lines combined with DIO-AV-ChR2. We then selectively activated either D1+ or D2+ MSNsuring cocaine conditioning in a conditioned place preference test,

behavioral paradigm that provides an indirect measure of reward.his study demonstrated that activating D1+ MSNs with 10 Hz fre-uency stimulation resulted in enhancement in preference for aub-threshold dose of cocaine (5 mg/kg), a dose that did not elicit

response in D1-Cre mice expressing the control DIO-AAV-EYFPirus. In contrast, the 10 Hz activation of D2+ MSNs attenuatedreference for 7.5 mg/kg cocaine [49]. Moreover, we also used aon-selective Herpes Simplex Viral (HSV) ChR2-mCherry vector toxpress the ChR2 in all NAc neurons. Mice receiving non-selectivexcitation of the NAc displayed enhanced preference for cocaine5 mg/kg) suggesting an overriding direct pathway effect. This isonsistent with a recent study which used AAV vectors to non-electively express, in all neurons of the NAc core in rats, either thehird generation halorhodopsin chloride pump (eNpHR3.0) or thecrhaerhodopsin proton pump (ArchT). This study demonstratedhat inhibition of NAc core neurons attenuated cocaine seeking dur-ng reinstatement, by either cue + drug or drug alone [71]. The rolef these two subtypes of MSNs in the core vs. shell of NAc remainsargely unanswered due to technical limitations, including the rela-ive difficulty in targeting these discrete areas in mouse. However,ith the recent development of rat BAC transgenic lines, studies

xamining these striatal subtypes in core vs. shell, during com-lex operant behaviors such as drug self-administration are on theorizon [47,72].

In our D1+ and D2+ NAc MSN cocaine study we also evaluatedocomotor responses during activation of each MSN subtype. Unlikehe dorsal striatum, we found that activation of either MSN sub-ype in NAc did not alter locomotor activity. However, mice thateceived repeated doses of cocaine (15 mg/kg) displayed enhancedocomotor responses when D1+ MSNs where activated with opto-enetics, 24 h after the last dose of cocaine [49]. This data suggests

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

hat direct pathway NAc neurons are sensitized to activating stimulifter cocaine exposure. Recent studies using alternative method-logies to silence or ablate D1+ or D2+ MSNs [59,60,73] confirmedur optogenetic findings and the hypothesized actions of the direct

PRESSn Research xxx (2013) xxx– xxx

pathway neurons in promoting drug reward and/or drug locomo-tor responses, while indirect pathway neurons promoted oppositeresponses.

Recently, two groups have used selective optogenetic stimula-tion in D1+ and D2+ dorsomedial striatal MSNs to further examinetheir roles in reinforcement. Tai et al. used a spatial alternativeforced-choice switching task in D1-Cre and D2-Cre mice injectedwith AAV-DIO-ChR2 in the dorsomedial striatum (dmStr) [74].Briefly, the task contained left or right nose poke triggers that werealternatively assigned as the active trigger, to a reward port forwater, within sessions. To inform their choices in the task, micerelied on recent reward history to assess whether water would bedelivered from one of two reward ports. Unilateral stimulation (10and 20 Hz bursts) of D1+ MSNs caused a shift toward the triggercontralateral of the dmStr side stimulated, while D2+ MSN stim-ulation (3, 10, and 20 Hz burst) shifted animals toward triggersipsilateral of stimulation. The authors conclude that these spatialselection biases were shifts in action value and suggest that activityin distinct populations of striatal neurons exerts opposing biases onthe selection of goal-directed responses [74]. Kravitz et al. also usedD1-Cre and D2-Cre mice, transfected with AAV-DIO-ChR2, whichwere placed in operant chambers that contained capacitive touchtriggers; one that activated a blue laser and the other inactive [75].Stimulation of D1+ MSNs in dmStr resulted in persistent increasedlight paired trigger contacts while D2+ MSN activation caused atransient decrease in light paired trigger contacts. Interestingly,dopamine antagonists did not prevent these behaviors. This studyalso demonstrated that D1+ dmStr MSN activation promoted placepreference for a laser paired chamber, whereas no place prefer-ence or aversion was observed after D2+ dmStr MSN activation[75]. Unlike this study, we were unable to drive a place prefer-ence for a laser-paired chamber in the absence of rewarding stimuli(i.e. cocaine) [49]. These discrepancies could be accounted for bydifferences in laser frequency, and laser duration (time on/off),varying opsin expression, or to the targeting of different striatalregions (dmStr vs. NAc) and their differential afferent and efferentconnections. The Kravitz, et al. study demonstrated that very lowdoses of DA antagonists did not alter the operant reinforcing behav-iors whereas our study showed a direct modulation of cocaine(which directly blocks DA reuptake from the synapse and stronglyincreases striatal dopamine) rewarding behaviors. Future studiesexamining optogenetic manipulation of dStr in the presence ofcocaine or other psychotsimulants will be necessary for a directcomparison between dStr and NAc.

Other groups have used optogenetics to examine MSN connec-tivity within the striatum and MSN connectivity to striatal outputnuclei. Using a mouse expressing ChR2 non-selectively in bothMSN subtypes, Chuhma et al. demonstrated that MSNs connect toother MSNs and TANs but do not directly connect to FS interneu-rons. Furthermore, this study and another optogenetic MSN studydemonstrated that MSNs project predominately to GABAergic com-pared to dopamine cells in the SN [76,77]. However, a recentstudy demonstrates that the larger striatal matrix compartmentsproject to GABA midbrain neurons whereas the smaller striosomecompartments project mainly to dopamine neurons [36]. Consis-tent with D1+ MSNs projecting to midbrain the Chuhma, et al.study demonstrated that MSNs connecting to the SN displayedD1 receptor mediated facilitation; whereas MSN connections toglobus pallidus display D2 receptor mediated presynaptic inhibi-tion. Finally, we recently used micro positron emission tomography(microPET) with [18F] 2-fluoro-2-deoxy-D-glucose (FDG) to mea-sure changes in regional brain glucose metabolism in response to

ights into striatal function and behavior. Behav Brain Res (2013),

ChR2 optogenetic stimulation of the nucleus accumbens (NAc) inawake rats. We found regional changes of enhanced or decreasedbrain glucose metabolism in NAc connected regions and many ofthese activated regions correlated well with c-Fos induction after

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ptogenetic activation of NAc [78]. Future studies using such imag-ng techniques with selective activation of NAc MSN subtypes ornterneurons will be extremely informative to understand the cir-uit wide effects of activating selective striatal cell populations.inally, studies examining MSN specific connections, within andutside of the striatum, during striatal behaviors will be importantn defining the striatal connectome in behavioral encoding.

. Striatal interneurons

The striatal interneurons comprise roughly 5% of all neuronsn this region but despite their small number, studies demon-trate a very important role for these interneurons in BG behavioralutput and function. Many optogenetic studies have providednsight into the role of the TANs in striatal function and behavioralncoding. These large choline acetyltransferase (ChAT) positiventerneurons were previously implicated in reward prediction, taskttention, memory, addiction, and aversive behaviors [14,79–82].itten et al. used the BAC transgenic ChAT-Cre mice to selec-

ively drive or inhibit TANs by expressing either ChR2 or eNpHR3.0n NAc during cocaine reward. They demonstrated that inhibitingNpHR3.0 expressing TANs with continuous yellow light duringocaine place conditioning (20 mg/kg) significantly decreased pref-rence for the cocaine-paired chamber [51]. Interestingly, theyemonstrated that yellow light photoinhibition of TANs express-

ng eNpHR3.0 caused most striatal neurons to be activated whileoughly 24% of sites measured displayed inhibition. In contrastctivating TANs using ChR2 (10 Hz blue light) predominantly sup-ressed firing in most NAc MSNs, however a subset of MSN’s19%) were activated. Activation of TANs also did not alter cocaineonditioning. This study demonstrated the behavioral contribu-ion of these interneurons in cocaine reward and suggests a roleor TANs in mediating MSN firing, which in turn regulates BGutput pathways. It will be interesting to determine if TANs pref-rentially synapse onto on D2+ MSNs since activation of theseSNs attenuates cocaine reward and mediates aversive responses

49,83].Higley et al. found that selective activation of TANs with ChR2

licited vGluT3 dependent glutamatergic transmission, specif-cally by observing glutamatergic currents in MSNs [84]. Inontrast, English et al. found that activating ChR2 expressingANs strongly inhibits MSNs via observed optogentically elicitedPSCs. They further mimicked the pause-excitation sequence pre-iously observed in TANs by temporal inhibition with eNpHR3.0o demonstrate that the pause-excitation in TANs inhibited

SN activity in freely moving animals [85]. These opposingndings of TAN excitation can be partially explained by the find-

ngs from the English et al. study demonstrating optogenticallylicited EPSCs in neuropeptide Y expressing striatal interneu-ons, which were highly correlated with the observed MSN IPSCs85].

Future studies manipulating the pause-excitation neuralynamics in vivo during reinforcement would be interesting sincerevious studies implicate TANs in encoding cue salience infor-ation in reinforcing and aversive behaviors [13,86]. Two recent

apers further confirmed the function of TANs in processes rel-vant to motivation by examining phasic dopamine release afterhR2 activation of TANs. Slice voltammetry studies demonstratedopamine release in the NAc or dStr after ChR2 expressing ChATells were selectively excited with a single pulse [87] or at 10 Hzulse trains [88]. Depolarization of the TANs also resulted in reliable

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

A spikes in vivo in anesthetized animals [88]. These findings fur-her implicate a role for TANs in reward behavior by their actions onopamine release. Future studies investigating optogenetic modu-

ation of dStr or NAc TANs in operant behaviors can provide further

PRESSn Research xxx (2013) xxx– xxx 5

insight into their function in reinforcement and motivation. Newlygenerated ChAT-Cre rat BAC transgenic lines will be instrumentalin such studies [47].

Optogenetic manipulation has recently been used in the fastspiking (FS) parvalbumin (PV) GABAergic interneurons in wholecell slice physiology. PV-Cre transgenic mice were transfected withDIO-AAV-ChR2 and optical excitation of FS interneurons createdrobust inhibitory responses onto MSNs. The same optogenetic exci-tation of FS interneurons displayed minimal inhibitory responsesin TANs, with a small proportion of low-threshold spiking LTSinterneurons showing inhibitory responses [89]. Future studiesusing in vivo optogenetic control of FS interneurons will helpto parse out the role of these interneurons in striatal dependentbehaviors.

4. Striatal afferents

The optogenetic toolbox has been extensively utilized toresearch striatal afferent connections. Many of these studies focuson how such connections influence reward-related behaviors.Direct dopamine signaling released from varicosities of dopami-nergic VTA projections is directly involved in reward predictionand addiction initiation [90,91]. This dopamine release differen-tially influences the two MSNs due to differential GPCR signalingthrough D1 vs. D2 receptors, leading to overall enhanced drive ofthe direct pathway and inhibition of the indirect pathway [92].Many of the original optogenetic behavioral studies focused ondirect manipulation of dopaminergic (DA) VTA neurons, whichare the main DA inputs to NAc, by utilizing TH-Cre mouse or ratknock-in lines combined with DIO-AAV-ChR2. These studies exam-ined phasic dopamine neuron stimulation that is characterized byirregular pacemaking single spike activity interspaced with rapidbursts of typically 2–6 spikes in rapid succession [93] in behavioralencoding. Tsai, et al. demonstrated that ChR2 activation inductionof phasic firing of VTA DA neurons using ChR2 led to a positiveconditioned place preference [56]. Although they did not evaluateVTA-NAc specific projections in this behavior, they demonstrated,using voltammetry, that optogenetic phasic firing of VTA DA neu-rons enhances dopamine release in NAc. This confirmed the directeffect of VTA dopamine release in the NAc in rewarding behaviors[94]. Furthermore, Adamantidis, et al. showed that phasic opticalstimulation of VTA DA neurons in behaving TH-Cre mice express-ing the DIO-ChR2 vector led to facilitation of reinforcing foodseeking behavior and elicited food seeking reinstatement alonewithout any other cues [95]. Future work investigating the func-tional role of projection specific DA neurons to striatal regionsand other brain regions in drug and natural reward will be veryimportant in distinguishing the differential behavioral functionsof DA neuron subpopulations since aversive or rewarding stim-uli alter excitatory synapses in these different DA subpopulations[96].

Koo, et al. recently investigated VTA inputs in NAc in morphinerewarding behaviors. Using non-selective AAVs to express ChR2 inVTA terminals, which predominantly colocalized with TH expres-sion, these authors demonstrated that phasic activation of theseterminals in the NAc enhanced morphine conditioned place pref-erence. Additionally, after blocking morphine place preference byinjecting BDNF into the VTA, the authors could reverse this bluntedmorphine reward with ChR2 phasic stimulation of VTA inputs inNAc [97]. Chaudhury et al. used TH-Cre mice combined with DIO-AAV-ChR2 to phasically stimulate DA cells in the VTA during a social

ights into striatal function and behavior. Behav Brain Res (2013),

defeat stress paradigm, which can induce persistent depression-like behaviors in mice [98–100]. They demonstrated that phasicactivation but not tonic activation of VTA DA neurons induced a sus-ceptible phenotype as observed by decreased social interaction and

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ucrose preference after a subthreshold social defeat protocol. Pha-ic stimulation also rapidly induced the depression-like phenotypen animals previously displaying resilient behaviors after a 10-dayocial defeat stress protocol. They also examined VTA DA projec-ion specific neurons by using a retrograde viral Cre dependentseudorabies virus (PRV-Cre), which they injected into the NAc oredial prefrontal cortex (mPFC) to selectively express Cre com-

ined with DIO-AAV-ChR2 or DIO-AAV-eNpHR3.0 in VTA-NAc vs.TA-mPFC projection DA neurons. They demonstrated that phasicctivation of VTA-NAc DA neurons is responsible for the susceptiblehenotype. They further demonstrated that inhibition of VTA-NAcA neurons in mice that were susceptible to the 10-day repeated

ocial defeat stress could shift these mice into a resilient phenotype.n contrast, selective inhibition of VTA-mPFC DA neurons resultedn a susceptible phenotype after subthreshold social defeat stress100].

Tye et al. demonstrated opposing findings in the role of VTAopaminergic firing using a different model of depression. First,sing TH-Cre mice injected with DIO-AAV-eNpHR3.0 to the VTA,hey demonstrated that optogenetic inhibition of VTA DA neuronsaused depression-like behaviors as observed by decreased timetruggling in the tail suspension test and decreased sucrose pref-rence. They then demonstrated that phasic stimulation of ChR2xpressing VTA DA neurons rescued depression-like phenotypes,nduced by a chronic mild stress protocol, as observed by enhancedime spent struggling in tail suspension and enhanced sucrose pref-rence. They showed that the antidepressant responses to phasictimulation could be reversed by pharmacological blockade of DAeceptors in the NAc. Furthermore, using TH-Cre BAC transgenicats (see discussion below) they were able to perform single unitecordings of NAc neurons during forced swim test coupled withTA DA phasic stimulation. TH-Cre rats, that underwent chronicild stress, elicited increased behavioral kicks in the forced swim

est during real time phasic firing of VTA DA cells and this wasoupled to increased or decreased firing of individual NAc neurons101]. These opposing findings of phasic VTA DA neuron stimula-ion in depression-related behaviors in the two studies could likelyeflect the different stressors (social defeat vs. chronic mild stress)sed in each study as previous work demonstrated differential DAeuron firing to different forms of stress [102]. Future studies willeed to address whether the phasic DA firing in both stress condi-ions have similar or differential effects on the various NAc neuronalubtypes.

Other groups are beginning to use rats in these optogenetictudies. Bass et al. used voltammetry, to demonstrate the abil-ty to drive dopamine release in the NAc of rats by non-selectiveptogenetic phasic firing of VTA cells [103]. A follow up study com-ared optical and electrical stimulation of dopamine release in thetriatum and found that classical electrical stimulation was ableo induce more dopamine release while optogenetic stimulationas more sensitive to stimulation pulse variations [104]. Witten

t al. recently developed TH-Cre BAC transgenic rats to selectivelytimulate DA cell bodies in the VTA in freely moving animals. TH-re rats, selectively expressing ChR2 in VTA DA neurons, werelaced in an operant chamber and trained to nose poke for pha-ic stimulation to VTA DA neurons. The group demonstrated thatats robustly self-stimulate for VTA DA neuron phasic stimulation,hich is accompanied by DA release in the NAc [47]. They subse-

uently used these rats in depression-related studies as discussedbove [101].

Two recent studies investigated a role of VTA GABAergic projec-ions to NAc in reward consumption and seeking. van Zessen et al.

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

sed vesicular GABA transporter (vGAT)-Cre mice to selectivelyxpress ChR2 in the VTA GABA neurons and then activated theseeurons at specific time points during a presentation of a reward.heir study demonstrated that stimulation of these inhibitory cells

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immediately following presentation of the reward led to disrup-tion in reward consumption. However, this study showed that VTAGABAergic projections to the NAc did not play a role in this observeddisruption but instead VTA GABAergic inhibition directly onto VTADA neurons drives this behavior [105]. They did however demon-strate the indirect effects of GABA VTA neurons on NAc by decreasedDA release into NAc, after inhibition of GABA VTA neurons. Tan et al.used a similar approach, with GAD-Cre mice to selectively expressChR2 in GABA positive neurons in the VTA. They demonstrated aconditioned place aversion after activation of VTA GABAergic neu-rons since GAD-Cre animals expressing ChR2 significantly avoidedthe chamber previously paired with the blue light, compared tocontrol conditions. They suggest this reflects GABAergic inhibitionof VTA DA neurons rather than inhibition to NAc since inhibitingVTA DA neurons expressing eNpHR3.0 in TH-Cre mice produces asimilar place aversion [106].

Another recent study used optogenetics to manipulate the affer-ents to the VTA in a conditioned place preference paradigm. Usinga retrograde rabies viral vector expressing ChR2 they were ableto identify and optogentically drive VTA afferents from the lat-erodorsal tegmentum (LDT) and the lateral habenula (LHb). Theydemonstrated that LDT neurons synapse onto DA neurons in thelateral VTA that send projections to the NAc while LHb neuronssynapse on VTA DA neurons in the medial VTA that send projectionsto the prefrontal cortex (PFC). The authors demonstrated that LDTstimulated mice displayed a place preference for the light pairedchamber whereas LHb stimulated mice showed a place aversion.Administration of dopamine antagonists selectively in the NAc wasable to block the place preference created by stimulation of LTDprojections to the VTA [107]. The findings of the LTD-VTA-NAccircuit in positive reward are consistent with other optogeneticstudies examining VTA-NAc reward and function [47,49,56,97], butprovide novel insight into more complex circuit levels by investi-gating these VTA afferents.

Other studies have focused on the role of glutamatergic affer-ents to the striatum. Stuber et al. used AAV vectors expressing ChR2under the CAMKII� promoter to selectively stimulate or inhibitthe excitatory projections to NAc. They demonstrated that miceself stimulate for 20 Hz light induced excitation of glutamater-gic projections from basolateral amygdala (BLA) to the NAc butdo not self stimulate for activation of PFC projections to the NAc.The group further demonstrated that inhibition of BLA-NAc fibersexpressing eNpHR3.0 blocked reward consumption [108]. In a morerecent study, Britt et al. demonstrated enhanced evoked EPSCs andlarger peak inward NMDAR mediated currents in the NAc MSNsafter optogenetic stimulation of CAMKII�–ChR2 expressing ven-tral hippocampus (vHipp) inputs compared to stimulation of theBLA and PFC inputs. They further demonstrated that cocaine expo-sure selectively strengthens vHipp synapses in the medial NAcshell and that bidirectional optogenetic control of vHipp termi-nals in the NAc can alter cocaine-induced locomotion. Finally, theydemonstrated that a 6 Hz optogenetic stimulation of vHipp, BLA,and mPFC glutamatergic inputs to the NAc caused a preferenceto a laser paired chamber. In addition, ChR2 stimulation of vHippand BLA (20 Hz) and PFC (30 Hz) projections in the NAc was suf-ficient to drive optical self stimulation. Their studies indicate thatweaker synapses, including those from the PFC, can drive motivatedbehaviors when a stronger optical stimulus was elicited indicatingthat the specific excitatory pathway activated is not as relevantas the amount of glutamate released into the NAc in generatingsuch behaviors [109]. These studies did not examine the com-bined effects of cocaine and PFC optogenetic activation. However

ights into striatal function and behavior. Behav Brain Res (2013),

a recent study used ChR2 optogenetic activation of PFC inputs toNAc in animals exposed to cocaine. They show enhanced presynap-tic release probability of the PFC-to-NAc synapses after short-termwithdrawal (1 d) and long-term (45 d) withdrawal from either

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oncontingent (i.p. injection) or contingent (self-administration)xposure to cocaine [110]. It is unknown whether the effects ofocaine on the glutamatergic inputs to the NAc in these previoustudies are occurring on a selective NAc MSN subtype. A recenttudy provides insight into this by demonstrating that optoge-etic activation of hippocampal afferents onto striatal MSNs areuch weaker onto D2+ MSNs. In contrast, glutamatergic inputs

rom the PFC and thalamus targeted D1+ and D2+ MSNs equally111].

Covington et al. investigated PFC activation in mice afterocial defeat stress and showed that high frequency bursting toFC neurons expressing HSV-ChR2-mCherry is anti-depressant, asbserved by reversal of the social avoidance and anhedonia behav-ors normally displayed in mice susceptible to social defeat stress112]. This study did not distinguish between glutamatergic orABAergic cell populations in the PFC nor did it examine the effectn PFC inputs to NAc. However, a follow up study used the Thy1-hR2 transgenic line, which selectively expresses ChR2 in layer

pyramidal neurons of the cortex, to optically stimulate the PFClutamatergic projection neurons in affective behaviors and thenxamine neural activity in limbic brain regions with this stimu-ation. Optogenetic stimulation of layer V pyramidal PFC neurons

as able to promote anti-depressant like responses in forced swimest but did not reverse social avoidance after social defeat stress.owever the optical stimulation did rescue the anxiety-like behav-

or exhibited in mice after social defeat stress. The authors furtheremonstrated with multi unit recordings that activating these layer

glutamatergic PFC neurons entrains neural oscillatory activitynd drives synchrony across limbic brain regions including the NAc113]. These studies have relevance to the antidepressant effects ofigh frequency Deep Brain Stimulation (DBS) to cortical regions inatients with treatment resistant depression [114]. Future studiesargeting PFC projections and other glutamatergic afferents to NAc,sing CAMKII� promoter viruses in animal models of depressionill be essential for understanding how these striatal glutamatergic

fferents encode depression-like behaviors or mediate antidepres-ive responses.

. Optogenetic tools to investigate molecular mechanismsf striatal behaviors

Researchers are beginning to examine molecular correlates ofehavioral actions after controlling neuronal firing with optoge-etics. For instance our group demonstrated that disrupting BDNFignaling in D1+ and D2+ MSNs mimics optogenetic activation ofhese neurons in cocaine reward. Moreover, we showed that down-tream BDNF signaling molecules, phopshoErk1/2, were decreasedollowing ChR2 activation of D1+ MSNs [49]. Koo, et al. also demon-trated that the blunted morphine rewarding effects of BDNF in VTAre reversed by phasic ChR2 optogenetic stimulation of VTA termi-als in NAc [97]. Likely we will see many new studies examiningolecular adaptations occurring after optogenetic manipulation

f striatal mediated behaviors or the utilization of optogeneticso rescue behaviors altered by genetic manipulation. Such stud-es are useful in understanding the underlying molecular pathwaysesponsible for brain disease and will aid in the understanding ofhe adaptive molecular responses that occur in treatments such asBS.

Additionally, the next generation of optogenetic tools is promis-ng for dissecting the molecular mechanisms, driving behavioralctions, with temporal resolution. The optogenetic toolbox has

Please cite this article in press as: Lenz JD, Lobo MK. Optogenetic inshttp://dx.doi.org/10.1016/j.bbr.2013.04.018

xtended beyond the activating and inhibiting opsins. Researchersre generating light activate G-protein coupled receptors (GPCR’s),ell signaling molecules, and transcription factors [115–119]. Airan,t al. developed and utilized GPCR optical proteins in behavior. They

PRESSn Research xxx (2013) xxx– xxx 7

used protein chimeras containing the photoactivatable domainsof rhodopsin with the intracellular domains of �2- or �1 adren-ergic GPCR’s which they coined OptoXRs [115]. The researcherswere able to initiate Gs adenylyl cyclase signaling or the phospho-lipase C signaling by activating the �2- adrenergic OptoXR or the�1-adrenergic OptoXR respectively with 473 nm blue light. Theyexpressed these OptoXRs in NAc to demonstrate that activation ofopto-�1AR was sufficient to promote a positive place preferencefor the light paired chamber [115]. This study provided insight intothe role of adrenergic signaling in the NAc in reward seeking anddemonstrated the utility of OptoXRs in controlling GPCR signalingon a temporal scale during behavioral conditioning.

Other groups are utilizing the LOV (light oxygen voltage)domain, which allosterically inhibits proteins fused to this domainin the dark. Upon blue-light exposure, a helix linking LOV tothe protein unwinds and thus allows the protein to perform itsnormal biological functions. Dietz, et al. examined the role ofRac1, a Rho GTPase, in cocaine structural plasticity and rewardby using a LOV domain Rac1 fusion protein [116,117]. The LOVdomain binds and blocks the ability of the Rac1 protein to bindto downstream effectors. Upon blue light exposure, the sterichindrance of a constitutively active Rac1 is released, allowingRac1 to perform downstream cellular functions including alteringcytoskeleton remodeling [118]. This study demonstrated that bluelight activation of LOV-Rac1 in the NAc during cocaine exposureblocked cocaine induced MSN dendritic plasticity. Furthermore,activation of LOV-Rac1 in NAc only during the cocaine condition-ing was sufficient to block cocaine place preference conditioning[116]. This is a powerful display of the use of optogenetic toolsto directly manipulate specific cell signaling cascades at precisetime points in drug exposure or behavioral paradigms. Given thedynamic progression of drug abuse and other neuropsychiatricdiseases over time, which could reflect different molecular mecha-nisms governing specific time points or symptoms throughout thedisease progression; the ability to manipulate molecular functionson a temporal scale can provide novel insights into the molecularcorrelates of psychiatric disease progression.

6. Conclusion and future directions

In the past five years optogenetic tools have provided extensiveinsight into the functional roles of striatal neuron subtypes and stri-atal efferent and afferent connections in complex behaviors. Giventhe complex heterogeneity of the striatum, the ability to targetprecise neuronal populations and projections and then manipulateactivity in these discrete circuits with light has provided a founda-tion for future optogenetic striatal studies. Such studies should beaimed at understanding basic behaviors and function in the stri-atum, as well as complex psychiatric diseases and neurologicaldisorders characterized by dysfunctional striatal circuitry.

With the introduction of OptoXRs, the photoactivatable LOVdomain, and other photoactivatable signaling molecules, such asnucleotidyl cyclases [116,117,120–122] researchers can now dis-creetly dissect, with temporal resolution, how molecular signalingcascades that are implicated in striatal function and disease canalter complex behaviors and disease progression. This could includepossible manipulations of many implicated molecules, includingBDNF signaling molecules, D1 receptor mediated adenylyl cyclasesignaling, D2 receptor mediated adenylyl cyclase inhibition, andcannabinoid signaling cascades [49,123,124]. For instance, OptoXRsfor dopamine receptors and cannabinoid receptors, as well as pho-

ights into striatal function and behavior. Behav Brain Res (2013),

toactivatable intracellular signaling proteins implicated in drugaddiction could be exploited to control these molecules dur-ing specific behavioral time points throughout the induction andexpression of addiction behaviors.

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An important caveat in moving forward with in vivo opticaltimulation is the possible indirect effects the light itself may beaving; as highlighted by the observation of single unit responsesfter retinal alone laser stimulation [125]. It is also important toote the limitations to ChR2 studies as the supraphysiological

nduced neuronal firing by ChR2 may elicit behavioral responseshat would not occur under normal physiological conditions, thusuch studies must be interpreted with caution. Over-excitation ofpecific cell types and circuits in the striatum might activate orilence different pathways that are not typically recruited duringormal physiological conditions. An example of this could includever exaggerated inhibition of the opposing direct or indirect MSNathways during selective activation of the other pathway. Indeed

recent study examining MSN subtype activation with in vivo realime Calcium detection shows activation of both direct and indirect

SNs during motor initiation in free moving animals [126]. Thistudy is consistent with basal ganglia models that predict balancedoordination between the two pathways to elicit normal behav-oral output. Nonetheless, optogenetic manipulation of each MSNubtype or other striatal cells can be used to model abnormal behav-oral output that reflect an imbalance of striatal circuits such as

otor disorders [50] or behavioral responses to drugs of abuse forxample cocaine which itself is a potent stimuli for selective striatalell subtypes [49].

Relevant behavioral paradigms should also be considered forhese optogenetic studies in the striatum. Many of the original opto-enetic reward studies relied on indirect measures of reward suchs conditioned place preference. However, recent studies are exam-ning more complex operant behavioral paradigms including drugelf-administration and reinforcement seeking operant behaviors,hich are relevant to the human condition of reward seeking

nd drug taking. Such behavioral tests were originally adaptedor rats, although researchers are able to perform these oper-nt behaviors in mice [75,105,108,127–129]. Nonetheless, recentevelopment of BAC transgenic rat lines will be especially use-ul in such studies [47]. Further optogenetic manipulations of thetriatum in non-human primates will be beneficial to understand-ng striatal function in more complex striatal dependent behaviors130]. Indeed a recent study demonstrated the feasibility of suchn approach by in vivo ChR2 elicited responses in the putamen andther basal ganglia structures in non-human primates [131]. How-ver, molecular tools including promoter based viral vectors will berucial for selectively targeting striatal cell subtypes in non-humanrimates or other animal models that lack transgenic models.

A final consideration for these optogenetic tools is the abil-ty to connect to clinical applications relevant to striatal basediseases including depression, drug addiction, Huntington’s Dis-ase, Parkinson’s Disease, obsessive compulsive disorders, andourette’s Syndrome. Mimicking the effects of high frequencyBS, which has been shown to be an effective treatment in manyiseases noted above [132–136] in specific striatal neuron popu-

ations or afferent and efferent connections, will be extremelyseful for a more conclusive understanding of the mechanisms ofBS, which are currently unclear. Newer ChR2 variants suited forigher frequency activation will be particularly useful [137]. As theptogenetic toolbox continues to expand with newer opsins andolecular signaling tools we will likely see a similar expansion

triatal optogenetic behavioral research leading to novel insightsn striatal behavior and disease.

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