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On the anniversary of the Boyden et al. (2005) paper that introduced the use of channelrhodopsin in neurons, Nature Neuroscience asks selected members of the community to comment on the utility, impact and future of this important technique.

There is disagreement on how best to define and investigate fear. Nature Neuroscience asked Dean Mobbs to lead experts from the fields of human and animal affective neuroscience to discuss their viewpoints on how to define fear and how to move forward with the study of fear.

Some people earn rewards more successfully when performing goal-directed tasks, but the neuronal changes that could mediate this reward-directed learning are not well understood. Rats were trained to self-administer a sucrose reward, and it was shown that reward learning depends on increased activity and synaptic strength in the amygdala, a brain region important for emotional learning. The level of learning attained by individual animals correlated well with the degree of synaptic strength enhancement.

Chronic Hepatitis B virus (HBV) is associated with elevated levels of hepatitis B surface antigen (HBsAg). Here the authors characterize the T cell responses to three variants of an HBsAg, Evn371-379, to find only the most stable L6I variant eliciting HBsAg responses, while T cells specific for L6I are detectable in both control and people with chronic HBV.

In mouse brain, neurotensin released into the basolateral amygdala by neurons in the paraventricular nucleus of the thalamus assigns positive or negative valence during associative learning.

Neurons in the basolateral amygdala projecting to canonical fear or reward circuits undergo opposing changes in synaptic strength following fear or reward conditioning, and selectively activating these projection-target-defined neural populations causes either negative or positive reinforcement, respectively.

Imaging and optogenetics in mice provide insight into the interplay between the primary motor cortex and the motor thalamus during learning, showing that thalamic inputs have a key role in the execution of learned movements.

The mechanisms by which methylphenidate (MPH or Ritalin) modifies behavioral performance are poorly understood. The authors show that MPH increased learning-induced strengthening of connections between the cortex and amygdala. This modulation was dependent on specific dopamine receptor subtypes.

Analyses of neural activity of mice competing in a social competition assay monitored by a computer vision tool reveal a neural circuit with a role in dynamically modulating social dominance.

Optogenetics enables the precise and targeted manipulation of the activity of specific neurons and is a powerful tool for the dissection of neural circuits. Tye and Deisseroth describe the latest refinements in optogenetic technology and show how this approach is being used to investigate the circuits involved in psychiatric and neurological disorders.

Different subregions of the bed nucleus of the stria terminalis are shown to increase and decrease anxiety in mice, and distinct neural projections arising from a single coordinating brain region modulate different anxiety features.

High-speed tracking of effortful responses and neuronal activity in rats during a forced swim test identifies medial prefrontal cortex (mPFC) neurons that respond during escape-related swimming but not normal locomotion, and optogenetics shows that mPFC neurons projecting to the brainstem dorsal raphe nucleus, which is implicated in depression, modulate this behavioural response to challenge

The amygdala, a brain region important for learning fearful memories, is thought to have a role in generalized anxiety, but the critical subregions and connections are unknown. This paper shows that optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala of rats with channelrhodopsin has an anxiolytic effect, whereas inhibition of the same projection with eNpHR3.0 increases anxiety related behaviours. These effects were not observed with direct optogenetic control of BLA somata themselves, indicating that selective activation of certain connections can have different effects.

Little is known about the mechanisms underlying the orchestration of competing motivational drives. During the simultaneous presentation of cues associated with shock or sucrose, when rats may engage in fear- or reward-related behaviors, amygdala neurons projecting to prefrontal cortex more accurately predict behavioral output and bias animals toward fear-related behavior.

A mechanistic understanding of anxiety is required to advance the development of next-generation therapies for anxiety disorders. In this Review, Calhoon and Tye discuss recent insights into the circuit physiology driving anxiety-like behavior gained through the application of modern approaches in neuroscience.

Through the use of a combination of state-of-the-art techniques, different populations of ventral tegmental area dopamine neurons in the mouse are shown to form separate circuits with distinct connectivity: neurons receiving input from the laterodorsal tegmentum and lateral habenula are found to mediate reward and aversion, respectively.

When people are isolated, they crave social interactions. Midbrain craving regions were activated by food in hungry people, and by social interactions in people mandated to be isolated.

Namboodiri, Otis et al. reveal that orbitofrontal cortex acquires and maintains a long-term memory of cue–reward associations to guide multiple aspects of behavioral learning, and that it routes select information to a downstream learning center.

Specific manipulation of midbrain dopamine neurons in freely moving rodents shows that their inhibition or excitation immediately modulates depression-like phenotypes that are induced by chronic mild stress, and that their activation alters the neural encoding of depression-related behaviours in the nucleus accumbens.

In this Analysis, the authors directly experimentally compare microbial opsins used for the control of neural activity. They extract essential principles and key parameters that can help end users with the design and interpretation of optogenetic experiments and guide tool developers in the characterization of future tools.

Dopamine in the medial prefrontal cortex modulates behavioural responses to aversive stimuli by increasing the signal-to-noise ratio of neurons projecting to the dorsal periaqueductal grey.

In this issue of Nature Neuroscience, Menegas et al. demonstrate a role for midbrain dopamine neurons projecting to the tail of the striatum in encoding stimulus novelty and threat avoidance. From this study emerges a model whereby distinct dopaminergic projections to striatum influence behavior along at least two axes, one representing value and one representing threat.

In this Technical Report, Chuong and colleagues introduce Jaws, an archaeon-derived, photoactivatable chloride pump that responds to red light. Owing to its efficiency in absorbing red photons and its large photocurrent, Jaws can be transcranially activated deep in the brain and thus allows noninvasive optogenetic silencing.

Social valence — the valence assigned to a social agent or social stimulus — is complex to compute. In this Review, Padilla-Coreano et al. explain how social attributes, social history, social memory, social rank and social isolation states are integrated to modulate social valence assignment.

Rabies viral vectors are important tools in neuroscience, but their cytotoxicity usually limits their use. Chatterjee et al. introduce a new class of double-deletion-mutant rabies viral vectors that leaves neurons alive and healthy indefinitely.

Ahmad, Lim, Morieri, Tam et al perform a systematic review and meta-analysis of biomarkers, genetic markers, and risk scores for prediction of cardiovascular outcomes in Type 2 diabetes. A few prognostic markers are identified that provide incremental predictive utility beyond established cardiovascular risk factors.