Optogenetics: illuminating the neural bases of rodent behavior

Figures & data

Table 1 Transgenic mouse lines used for optogenetic manipulation of behavior

	Promoter	Expression (cell type)	Opsin	Behavioral uses
Transgenic	nNOS	Molecular layer neurons (cerebellum)	ChR2(H134R)	Motor function^Citation80
lines	Thyl	Glutamatergic	ChR2(H134R)	Motor function,^Citation22,Citation79 anxiety^Citation116
Rodent lines +	AGRP-Cre	AGRP-expressing	ChR2(H134R)	Feeding^Citation15
Cre-inducible	CamKIIα-Cre	Glutamatergic	ChR2(H134R)	Anxiety^Citation118
AAVs			Arch	Anxiety^Citation118
	c-fos-tTA	Activated by c-fos induction	TRE-ChR2	Fear learning^Citation37,Citation38
	ChAT-Cre*	Cholinergic	eNpHR3.0	Reward^Citation93
	DAT-Cre	Dopamine	ChR2(H134R)	Reward^Citation100
	D1 -Cre, D2-Cre	Dopamine receptor expressing	ChR2(H134R)	Motor function,^Citation78 motivation,^Citation91,Citation125
		(MSN subtypes in the striatum)		reward,^Citation82,Citation84,Citation85,Citation87,Citation89 Feeding^Citation54
			eNpHR3.0	Reward,^Citation89 motivation,^Citation125 anxiety^Citation139
			ChR2(EI23A)	Mood^Citation92
	Emx-Cre	Glutamatergic	ChR2(H134R)	Anxiety/motivation^Citation128
	GAD65-Cre or	GABA-ergic	ChR2(H134R)	Motivation,^Citation109 reward^Citation111
	GAD65-IRES-Cre^#		Vertebrate Melanopsin-5-HT2c	Anxiety^Citation7
			Arch	Anxiety^Citation119
	Gal-Cre	Gal-expressing	ChR2(H134R)	Aggression^Citation153
	112b-Cre	GABA-ergic	ChR2(H134R)	Learning^Citation149
	L7/Pcp2-Cre	Purkinje	vertebrate Rhodopsin	Motor function^Citation58
	Pet1 -Cre	Serotoninergic	vertebrate Melanopsin-5HT2c	Anxiety^Citation7
	POMC-Cre	Immature DG cells	ChR2(H134R)	Learning^Citation148
			eNpHR3.0	Learning^Citation148
	PV-Cre	Parvalbumin	CIVI	Anxiety^Citation120
			ChR2(H134R)	Reward,^Citation122 epilepsy^Citation73
	Rgs9-Cre	Rgs9-expressing	ChR2(H134R)	Reward/pain^Citation162
	TH-Cre* or	Dopamine	ChR2(H134R)	Reward,^Citation30,Citation98,Citation99,Citation102,Citation113,Citation139 motivation,^Citation97
	TH-IRES-Cre^#			mood,^Citation40,Citation41,Citation107 sleep^Citation157
			eNpHR3.0	Mood,^Citation40,Citation107 sleep^Citation157
	Vgat-IRES-Cre^#	GABA-ergic	ChR2(H134R)	Reward^Citation110,Citation136
			eNpHR3.0	Reward^Citation136
	Vglut2-IRES-Cre^#	Glutamatergic	ChR2(H134R)	Anxiety/reward^Citation136

Notes: Transgenic lines that have been used in mouse and rat studies are denoted by an asterisk (*). Knock-in lines are denoted by a hashtag (#) and all lines not denoted by this symbol are transgenic lines.

Abbreviations: AAVs, adeno-associated viruses; AGRP, agouti-related peptide; tTA, tetracycline transactivator; D1, Dopamine 1; D2, Dopamine 2; IRES, internal ribosome entry site; POMC, pro-opiomelanocortin; Rgs9, regulator of G-protein signaling 9; MSN, medium spiny neuron; nNOS, neural nitric oxide synthase; PV, parvalbumin; TH, tyrosine hydroxylase; GABA, gamma-aminobutyric acid; DG, dentate gyrus; TRE, tetracycline response element; ChR2, channelrhodopsin 2; eNpHR3.0, enhanced third generation Natronomonas pharaonis.

Figure 1 Common schemes utilized for optogenetic manipulation of neuronal subtypes.

Notes:(A–D) Genetic opsin constructs are flanked by ITRs (gray box) and followed by an enhancer sequence (pink box). Promoters (pink arrow) drive cell-type specific expression. The ChR2 constructs (blue rectangle) are fused to an enhanced yellow fluorescent protein (EYFP; green arrow) for simple visualization under a microscope for electrophysiological recording or later immunohistochemical analysis. (A) An adeno-associated virus (AAV) containing ChR2 on a CamKII promoter infects excitatory neurons of prefrontal cortex (PFC) and travels down their axons, allowing for terminal stimulation in the nucleus accumbens (NAc). (B) An AAV containing a double inverted open (DIO) ChR2 construct is injected into the NAc of a mouse expressing Cre in Dopamine 1 (D1) receptor medium spiny neurons (MSNs). The opsin is double floxed by distinct flox sites (black and gray triangles). These two sites are recognized by Cre and the gene is spliced out, inverted, and re-ligated expressing ChR2 selectively in D1-MSNs. (C) A tetracycline (“Tet”) on (“Tet-off”) activated ChR2 is injected into a transgenic mouse that expresses a tet trans-activator (tTA) in response to c-fos activation. ChR2 is transcribed exclusively in the presence of c-fos-promoted tTA transcription when doxycycline (dox), an inactivator of tTA, is not present. With this strategy, previously active cells are optogenetically activated. (D) A pseudorabies virus (PRV) expressing Cre is injected in the NAc and retrogradely transports Cre up terminals in the NAc. A DIO-AAV construct containing ChR2 is injected into the ventral tegmental area (VTA) and is selectively expressed in cells that contain Cre following retrograde transport, allowing for selective optogenetic activation of VTA cells that terminate in the NAc.
Abbreviations: ChR2, channelrhodopsin 2; TRE, tetracycline response element; ITR, inverted terminal repeats; Hipp, hippocampus; PR, .

Table 2 Viral constructs utilized in optogenetic manipulation of behavior

Virus	Promoter	Expression	Opsin	Behavioral uses
Adeno-associated virus	CAG	All cells	ChR2(H134R)	Reward^Citation130
			ArchT	Reward,^Citation90 learning^Citation146
	CamKlla	Mostly glutamatergic	ChR2(H134R) eNpHR3.0 SFO ChR2(E 123A)	Mood,^Citation115,^Citation117 reward/motivation,^Citation123,^Citation127,^Citation129,^Citation131anxiety,^Citation139–Citation142 learning,^Citation145 epilepsy^Citation74 Reward/motivation,^Citation124,^Citation126,^Citation129,^Citation131 anxiety,^Citation139–Citation142 feeding^Citation133 Anxiety^Citation120
	CMV	Expression observed in serotonergic neurons	Vertebrate rhodopsin-5-HTIA	Learning^Citation146 Anxiety^Citation8
	hsyn	Neurons	ChR2(H134R) ReaChR eNpHR3.0	Pain,^Citation68 reward^Citation113 Motor function^Citation20 Pain,^Citation68 reward^Citation54,^Citation121
	MCH	MCH expressing hypothalamic neurons	ChR2	Sleep^Citation159
	TH	Dopamine	ChR2(H134R)	Reward/motivation^Citation102
Lentivirus	CamKHa	Glutamatergic	ChR2(H134R) NpHR2.0 eNpHR3.0	Motor function^Citation75,^Citation79 Epilepsy^Citation71 Motor function^Citation79
	HCRT	Hypocretin expressing cells	ChR2(H14R)	Sleep^Citation156–Citation158
	hsyn	Neuron-specific	opto-α1AR, opto-β2AR	Reward^Citation6
	sPRS	Predominantly catecholaminergic neurons, Phox2 expressing cells	ChR2(H134R)	Pain^Citation69
Herpes	CMV	High expression in neurons	ChR2(H134R)	Pain^Citation141
simplex	E4/5	Neuron-specific	ChR2(H134R)	Mood^Citation114
virus			LOv-Rac1	Reward^Citation12
Pseudorabies	RV	Presynaptic neurons	ChR2(H134R)	Reward^Citation39
virus	RV-Cre	Presynaptic neurons	DIO-ChR2, DIO-eNpHR3.0	Mood^Citation40,^Citation41

Abbreviations: CAG, CMV early enhancer/chicken beta actin; CMV, cytomegalovirus; MCH, melanin-concentrating hormone; TH, tyrosine hydroxylase; RV, rabies virus; SFO, step-function opsin; LOV, light-oxygen-voltage-sensing; HCRT, hypocretin; ChR2, channelrhodopsin 2; eNpHR3.0, enhanced third generation Natronomonas pharaonis; NpHR2.0, second generation Natronomonas pharaonis; DIO, double inverted open; ArchT, archeorhodopsin.

Table 3 Behavioral outcomes of in vivo optogenetic manipulation with channel opsins

Brain region	Stimulation site	Manipulation	Cell subtype	Behavior	Behavioral outcomes	References	Notes
BLA	Cell body region	Stimulation	Glutamatergic	Learning	Increased memory retention	145,146
		Stimulation	Non-specific	Pain	Hypersensitivity to pain	160
		Inhibition	Non-specific	Learning	Impairs learning	146,148
	BNST	Inhibition	Glutamatergic	Anxiety	Anxiogenic	139
	CeA, BNST	Stimulation	Glutamatergic	Anxiety	Anxiolytic	140
	CeA	Inhibition	Glutamatergic	Anxiety	Anxiogenic	140
	ILmPFC	Inhibition	Non-Specific	Learning	Enhanced learning	43
	PLmPFC	Inhibition	Non-Specific	Learning	Reduced learning	43
	NAc	Stimulation	Glutamatergic	Reward	Promotes reward	131
		Inhibition	Glutamatergic	Reward	Reduced responding to reward	131
	vHipp	Stimulation	Glutamatergic	Anxiety	Anxiogenic	141,142
		Inhibition	Glutamatergic	Anxiety	Anxiolytic	141,142
BNST	LH	Inhibition	Dl Receptor	Anxiety	Anxiolytic	139
		Stimulation	GABA-ergic	Feeding	Increased feeding	136
		Inhibition	Glutamatergic	Feeding	Suppresses feeding	136
Cerebellum	Cell body region	Stimulation	MLIs	Motor function	Produced fine motor movement	80
DSt	Cell body region	Inhibition	All neurons	Reward	Reduced amphetamine locomotion	54
		Stimulation	D1 -MSN	Motivation	Reduced action-value, reinforcing	82,91
		Stimulation	D1 -MSN	Motor function	Increased movement	78
		Stimulation	D2-MSN	Motivation	Enhanced action-value, aversive/promotes punishment	82,91
		Stimulation	D2-MSN	Motor function	Decreased movement	78
Hippocampus	CAI	Inhibition	Glutamatergic	Epilepsy	Inhibited epileptiform activity	73
	DG	Inhibition	II 2b cells	Learning	Prevents learning	149
		Stimulation	Neuron-specific	Learning	Stimulation of activated cells induces learned fear response, stimulation during conditioning blocks learning	37,38,148
		Stimulation	PV	Epilepsy	Inhibited epileptiform activity	73
	NAc	Stimulation	Glutamatergic	Reward	Promotes reward	129,130	Potentiation on D1 -MSNs from ventral hippocampal inputs
		Inhibition	Glutamatergic	Reward	Reduced locomotor sensitization	129	Ventral hippocampus projections
Hypothalamus	PVH	Stimulation	AGRP neurons	Feeding	Increased feeding	135	ARC cell stimulation
	LH	Stimulation	HCRT	Sleep	Induces wakefulness, fragments sleep	156-158
		Stimulation	MCH	Sleep	Increases sleep onset and NREM and REM	159
	HPOA	Stimulation	Gal neurons	Aggression	Increased aggression	153
LC	Cell body region	Stimulation	DA-ergic	Sleep	Induces wakefulness	157
		Inhibition	DA-ergic	Sleep	Enhances sleep	157
		Stimulation	Phox2 neurons	Pain	Altered pain response	69	LC subcompartment produced different outcomes
LDT	VTA	Stimulation	Non-specific	Reward	Promotes reward	39
LHb	VTA, RMTg	Stimulation	Non-specific	Reward	Blocks reward	39,1 12	Terminals likely synapse on DA cells
Motor cortex	Cell body region	Stimulation	Glutamatergic	Motor function	Increased movement	22,75
		Inhibition	Glutamatergic	Epilepsy	Inhibited epileptiform activity	71
NAc	Cell body region	Inhibition	ChAT	Reward	Reduced drug conditioned place preference	93
		Stimulation	DI-MSN	Reward/mood	Promotes reward, anti-depressant	84,87,89,92,100	Facilitated by NAc-VTA connection
		Stimulation	D1 -MSN	Pain/reward	Increases morphine tolerance	162
		Stimulation	D2-MSN	Reward/mood	Blocks reward, depressant	84,89,92,100
		Inhibition	Non-specific	Reward	Attenuates reinstatement	90
OFC	Cell body region DSt	Stimulation	Glutamatergic	Motivation	Increased goal-directed lever pressing	123
		Stimulation	Emx neurons	Mood/anxiety	Increased persistent grooming	128	Repeated stimulation
		Stimulation	Glutamatergic	Mood/anxiety	Alleviates compulsive grooming	127	Acute stimulation
mPFC	Cell body region	Stimulation	Dl receptor	Reward	Enhanced timing to receive reward	125
		Stimulation	Glutamatergic	Anxiety	Enhanced social interaction	1 16
		Inhibition	Glutamatergic	Motivation	Prevents habitual goal-directed actions, Disrupts fixed-interval timing task	124,125
		Inhibition	Glutamatergic	Reward	Increased social interaction	133
		Stimulation	Non-specific	Mood	Anti-depressant	1 14
		Stimulation	PL neurons	Reward	Decreased compulsive cocaine seeking	126
		Stimulation	PV	Anxiety	Increased social interaction	120
		Stimulation	PV	Reward	Extinction of cue-reward behavior	122
	BLA	Stimulation	Dl receptor	Feeding	Increased feeding	132
		Inhibition	Dl receptor	Feeding	Reduced feeding	132
		Stimulation	Glutamatergic	Mood/anxiety	Anxiolytic	115
	DRN	Stimulation	Glutamatergic	Mood/anxiety	Promotes social avoidance, anti-depressant	1 17,1 18
		Inhibition	Glutamatergic	Anxiety/mood	Decreased social aversion, prevents acquisition of social aversion	1 18,1 19
	NAc	Stimulation	Glutamatergic	Mood/anxiety	Anti-depressant	115
		Inhibition	Neuron-specific	Reward	Inhibited cocaine reinstatement	121
		Stimulation	Non-specific	Reward	Enhanced drug seeking	130	Depressed synapses on D1 -MSNs
	PLmPFC	Inhibition	Glutamatergic	Reward	Enhanced compulsive cocaine seeking	126
Sciatic nerve		Stimulation	Neuron-specific	Pain	Enhanced pain	68
		Inhibition	Neuron-specific	Pain	Blocked pain	68
STN		Stimulation	Glutamatergic	Motor function	Decreased rotations, enhanced locomotion	79
Thalamus		Inhibition	Glutamatergic	Epilepsy	Reduced epileptiform activity	74
VTA	Cell body region	Stimulation	DA-ergic	Reward/mood	Promotes reward	19,30,98, 99,101	Phasic stimulation is rewarding, while tonic stimulation blocks reward (similar to inhibition)
		Stimulation	DA-ergic	Mood	Depressant following social defeat stress	40,41
		Stimulation	DA-ergic	Mood	Anti-depressant following chronic mild stress	107
		Inhibition	DA-ergic	Anxiety/mood	Anti-depressant following social defeat stress	40
		Inhibition	DA-ergic	Mood	Depressant during depression assays	107
		Stimulation	GABA-ergic	Reward	Blocks reward and aversive	1 1 1
	NAc	Stimulation	DA-ergic	Reward/mood	Promotes reward, depressant following social defeat stress	40,41,100,102
		Inhibition	DA-ergic	Anxiety/mood	Anti-depressant	40
		Stimulation	GABA-ergic	Motivation	Increased descri mi nation of motivational stimuli	109
	mPFC	Inhibition	DA-ergic	Anxiety/mood	Reduced social interaction	40

Abbreviations: BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; ILmPFC, infralimbic medial prefrontal cortex; PLmPFC, prelimbic medial prefrontal cortex; MLI, molecular layer interneurons; DSt, dorsal striatum; LC, locus coeruleus; HPOA, hypothalamus-preoptic area; PV, parvalbumin; ARC, arcuate nucleus; REM, rapid eye movement; NREM, non-rapid eye movement; AGRP, agouti-related peptide; MCH, melanin-concentrating hormone; DA, dopaminergic; LDT, laterodorsal tegmental nucleus; LHb, lateral habenula; RMTg, rostromedial tegmental nucleus; OFC, orbitofrontal cortex; mPFC, medial prefrontal cortex; DRN, dorsal raphe nucleus; STN, subthalamic nucleus; VTA, ventral tegmental area; NAc, nucleus accumbens; vHipp, ventral hippocampal; DG, dentate gyrus; D1, Dopamine 1; D2, Dopamine 2; GABA, gamma-aminobutyric acid; MSN, medium spiny neuron.

Table 4 Behavior outcomes of in vivo optogenetic manipulation with signaling opsins

Brain region	Construct	Manipulation	Cell subtype	Behavior	Behavioral outcomes	References
Cerebellum	VRh (Gi/o)	Inhibition	Purkinje cells	Motor function	Altered motor coordination	58
DRN	VMo-5HT2C (Gq)	Signal transduction	GABA-ergic	Anxiety	Anxiolytic	7
		Signal transduction	Serotonergic	Anxiety	Anxiolytic	7
	VSWO 5HTIa (Gi/o)	Inhibition	Non-specific	Anxiety	Anxiolytic	8
NAc	Alphal-AR (Gs)	Stimulation	Non-specific	Reward	Increased drug conditioned	6
					place preference
	Racl	Protein activation	Non-specific	Reward	Increased place preference,	12
					sensitization

Abbreviations: DRN, dorsal raphe nucleus; NAc, nucleus accumbens; AR, adrenergic receptor; vRh, vertebrate rhodopsin; vMo, vertebrate melanopsin; vSWO, vertebrate short-wavelength opsin.

Figure 2 Optogenetically mimicking naturalistic neuronal firing differentially regulates cellular and behavioral outcomes.

Notes: (A–C) Example of stimulation paradigms to mimic naturalistic firing patterns of ventral tegmental area (VTA) dopamine (DA) neurons. (A) In vivo recording is used to determine naturalistic firing patterns of DA neurons. The example cartoon trace shows phasic bursts of VTA-DA neurons following social defeat stress. (B) In vitro slice recordings validate expression of the opsin and functional firing frequency during optogenetic stimulation. (C) In vivo phasic optogenetic stimulation of VTA-DA neurons promotes depression-like outcomes to social defeat stress, while tonic optogenetic stimulation reverses susceptibility.

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