This review, one of a series of articles, tries to make sense of optogenetics, a recently developed technology that can be used to control the activity of genetically-defined neurons with light. Cells are first genetically engineered to express a light-sensitive opsin, which is typically an ion channel, pump, or G protein–coupled receptor. When engineered cells are then illuminated with light of the correct frequency, opsin-bound retinal undergoes a conformational change that leads to channel opening or pump activation, cell depolarization or hyperpolarization, and neural activation or silencing. Since the advent of optogenetics, many different opsin variants have been discovered or engineered, and it is now possible to stimulate or inhibit neuronal activity or intracellular signaling pathways on fast or slow timescales with a variety of different wavelengths of light. Optogenetics has been successfully employed to enhance our understanding of the neural circuit dysfunction underlying mood disorders, addiction, and Parkinson’s disease, and has enabled us to achieve a better understanding of the neural circuits mediating normal behavior. It has revolutionized the field of neuroscience, and has enabled a new generation of experiments that probe the causal roles of specific neural circuit components.

Journeys to novel and familiar destinations employ different navigational strategies. The 1 first drive to a new restaurant relies on map-based planning, but after repeated trips the 2 drive is automatic and guided by local environmental cues 1,2 . Ventral striatal dopamine rises 3 during navigation toward goals and reflects the spatial proximity and value of goals 3 , but the 4 impact of experience, the neural mechanisms, and the functional significance of dopamine 5 ramps are unknown 4,5 . Here, we used fiber photometry [6][7][8] to record the evolution of activity 6 in midbrain dopamine neurons as mice learned a variety of reward-seeking tasks, starting 7 recordings before training had commenced and continuing daily for weeks. When mice 8 navigated through space toward a goal, robust ramping activity in dopamine neurons 9 appeared immediately -after the first rewarded trial on the first training day in completely 10 naïve animals. In this task spatial cues were available to guide behavior, and although ramps 11 were strong at first, they gradually faded away as training progressed. If instead mice 12 learned to run a fixed distance on a stationary wheel for reward, a task that required an 13 internal model of progress toward the goal, strong dopamine ramps persisted indefinitely. 14 In a passive task in which a visible cue and reward moved together toward the mouse, ramps 15 appeared and then faded over several days, but in an otherwise identical task with a 16 stationary cue and reward ramps never appeared. Our findings provide strong evidence that 17 ramping activity in midbrain dopamine neurons reflects the use of a cognitive map 9,10 -an 18 internal model of the distance already covered and the remaining distance until the goal is 19 reached. We hypothesize that dopamine ramps may be used to reinforce locations on the way 20 to newly-discovered rewards in order to build a graded ventral striatal value landscape for 21 guiding routine spatial behavior.The decision to continue pursuing a goal or abandon the quest depends on how much progress has 1 been made, how much remains to be done, and the value of the goal. For example, a climber will 2 be more deterred by rain at a mountain's base than near the summit, and will be more reluctant to 3 abandon a prized peak than a training hill. Information about progress toward goals and their value 4 is essential for adaptively balancing time and energy between activities, and commitment to goals 5 and the vigour of goal-directed actions are both regulated by goal progress and value 11-16 . 6 7Ventral striatal dopamine (DA) progressively rises as rodents navigate toward spatially distant 8 rewards 3 , a surprising recent finding that was not anticipated by temporal difference learning 9 models of DA function 4 but which has broadened our understanding of the role of ventral striatal 10 DA in sustaining and invigorating goal-directed behavior 17 . DA ramps reflect the value and 11 proximity of goals, scaling by the value of the reward and stretching or compressing in ...

Major depressive disorder can manifest as different combinations of symptoms, ranging from a profound and incapacitating sadness, to a loss of interest in daily life, to an inability to engage in effortful, goal-directed behavior. Recent research has focused on defining the neural circuits that mediate separable features of depression in patients and preclinical animal models, and connections between frontal cortex and brainstem neuromodulators have emerged as candidate targets. The development of methods permitting recording and manipulation of neural circuits defined by connectivity has enabled the investigation of prefrontal-neuromodulatory circuit dynamics in animal models of depression with exquisite precision, a systems-level approach that has brought new insights by integrating these fields of depression research.

Clinical researchers have tracked patients with early life trauma and noted generalized anxiety disorder, unipolar depression, and risk-taking behaviors developing in late adolescence and into early adulthood. Animal models provide an opportunity to investigate the neural and developmental processes that underlie the relationship between early stress and later abnormal behavior. The present model used repeated exposure to 2,3,5-trimethyl-3-thiazoline (TMT), a component of fox feces, as an unconditioned fear-eliciting stimulus in order to induce stress in juvenile rats aged postnatal day (PND) 23 through 27. After further physical maturation characteristic of the adolescent stage (PND 42), animals were tested using an elevated plus maze (EPM) for anxiety and plantar test (Hargreaves method) for pain to assess any lingering effects of the juvenile stress. To assess how an additional stress later in life affects anxiety and pain nociception, PND 43 rats were exposed to inescapable shock (0.8 mA) and again tested on EPM and plantar test. A final testing period was conducted in the adult (PND 63) rats to assess resulting changes in adult behaviors. TMT-exposed rats were significantly more anxious in adolescence than controls, but this difference disappeared after exposure to the secondary stressor. In adulthood, but not in adolescence, TMT-exposed rats demonstrated lower pain sensitivity than controls. These results suggest that early life stress can play a significant role in later anxiety and pain nociception, and offer insight into the development and manifestation of anxiety- and trauma-related disorders.

SUMMARYSurvival requires both the ability to persistently pursue goals and the ability to determine when it is time to stop, an adaptive balance of perseverance and disengagement. Neural activity in the lateral habenula (LHb) has been linked to aversion and negative valence, but its role in regulating the balance between reward-seeking and disengaged behavioral states remains unclear. Here, we show that LHb neural activity is tonically elevated during minutes-long disengagements from reward-seeking behavior, whether due to repeated reward omission or following sufficient consumption of reward. Further, we show that LHb inhibition extends ongoing reward-seeking behavioral states but does not prompt re-engagement. We find no evidence for similar tonic activity fluctuations in ventral tegmental area (VTA) dopamine neurons. Our findings implicate the LHb as a key mediator of disengagement from reward-seeking behavior in multiple contexts and argue against the idea that the LHb contributes to decisions solely by signaling aversion.

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Taiep (tremor, ataxia, immobility, epilepsy, paralysis) mutants show a significant increase in myelin thickness from 10 to 30 days of age but then demonstrate a decrease in myelin thickness from 1 to 6 months. The severity of the demyelination in the optic nerve suggests that visual deficits may exist in the taiep mutants. Animals were trained on a discrimination task, in which responses to a light stimulus (the S D period) were reinforced on a fixed ratio (FR)-1 schedule, and responses in the absence of the light stimulus (the S ∆ period) were not reinforced. Following training, the light intensity presented during the S D period was gradually reduced between sessions until −6.0 candela/m 2 was reached. Both groups of animals -taiep mutants and control Sprague Dawley rats -successfully recognized and responded in the presence of the stimulus near perfectly by the final day of training, suggesting that taiep mutants demonstrated normal learning, at least under this paradigm. Despite the severe demyelination of the taiep optic nerve, no visual deficits were detected as both groups of animals performed similarly as the light intensity decreased. Though the myelin loss of the optic nerve may have negatively affected signal transduction, this did not result in an increase in visual threshold.

Traditionally, the signaled avoidance (SA) paradigm has been used in an attempt to better understand human phobia. Animal models of this type have been criticized for ineffectively representing phobia. The SA model characterizes phobia as an avoidance behavior by presenting environmental cues, which act as warning signals to an aversive stimulus (ie, shock). Discriminated conditioned punishment (DCP) is an alternative paradigm that characterizes phobia as a choice behavior in which fear serves to punish an otherwise adaptive behavior. The present study quantifies the differences between the paradigms and suggests that DCP offers an alternative paradigm for phobia. Rats trained on either SA or DCP were compared on a number of behavioral variables relevant to human phobia. Results indicate that rats in the DCP paradigm responded significantly earlier to warning signals and were more effective at preventing shocks than rats in the SA paradigm. Implications of this alternative paradigm are discussed.