Table 2. Effect of optostimulation on behavioral expression and neural modulation.

Abbreviation: Self-stimulation: SS; excitatory postsynaptic potential: EPSP; dopamine: DA; Nucleus accubems: NAc; Ventral tegmental area: VTA; Dorsal Raphe Nuclei: DRN;

Opto or chemo-genetic stimulation (neuronal population targeted)	Location of optical fiber	Effects on reward-related behaviors	Biomarker effect	References
5-HT neurons (Tph2-tTA promoter[1, 2]; SERT promoter [3]; Pet-1 [4])	DRN	NOT reinforcing but Enhances patience for future rewards		[1-4]
5-HT neurons (Pet1 promoter)	DRN	↑SS	Firing activity during reward mediated by 5-HT and glutamate	[5]
5-HT neurons (Tph2 promoter)	DRN	↑SS and Place preference		[6]
5-HT neurons (Pet1 promoter)	DRN	↓Place Preference		[7]
5-HT neurons projection to VTA (Pet1 promoter) citalopram (5 or 10 mg/kg i.p.).	VTA	↓Operant response		[8]
DRN glutamatergic projection to VTA (Vglut3 promoter)	VTA	↑Operant response		[4, 9]
5-HT neurons (SERT promoter) and glutamatergic projections to VTA (Vglut3 promoter)	VTA	↑Place preference	Release of dopamine in the NAc mediated through AMPA and 5-HT3 receptors	[10]
DRN 5-HT projection to VTA (Pet1 promoter)	VTA	↑Locomotion	EPSPs on DA neurons blocked by AMPA receptor antagonist	[7]
DRN 5-HT projecting to amygdala (SERT promoter)		Anxiety like behavior	Activation by reward and punishment	[11]
DRN 5-HT projecting to frontal cortex (SERT promoter)		Increase active coping in face of challenge	Activation during reward and inhibited by punishment	[11]

Ref-erences.

^1.Miyazaki, K., et al., Reward probability and timing uncertainty alter the effect of dorsal raphe serotonin neurons on patience. Nat Commun, 2018. 9(1): p. 2048.

^2.Miyazaki, K.W., et al., Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards. Curr Biol, 2014. 24(17): p. 2033–40.

^3.Fonseca, M.S., M. Murakami, and Z.F. Mainen, Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing. Curr Biol, 2015. 25(3): p. 306–315.

^4.McDevitt, R.A., et al., Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry. Cell Rep, 2014. 8(6): p. 1857–1869.

^5.Liu, Z., et al., Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron, 2014. 81(6): p. 1360–74.

^6.Nagai, Y., et al., The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion. Int J Mol Sci, 2020. 21(6).

^7.Cunha, C., et al., Perinatal interference with the serotonergic system affects VTA function in the adult via glutamate co-transmission. Mol Psychiatry, 2020.

^8.Browne, C.J., et al., Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition. Neuropsychopharmacology, 2019. 44(4): p. 793–804.

^9.Qi, J., et al., A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons. Nat Commun, 2014. 5: p. 5390.

^10.Wang, H.-L., et al., Dorsal Raphe Dual Serotonin-Glutamate Neurons Drive Reward by Establishing Excitatory Synapses on VTA Mesoaccumbens Dopamine Neurons. Cell Reports, 2019. 26(5): p. 1128–1142.e7.

^11.Ren, J., et al., Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems. Cell, 2018. 175(2): p. 472–487 e20.