Optogenetics publications

Working memory (WM), the ability to actively hold information in memory over a delay period of seconds, is a fundamental constituent of cognition. Delay-period activity in sensory cortices has been observed in WM tasks, but whether and when the activity plays a functional role for memory maintenance remains unclear. Here, we investigated the causal role of auditory cortex (AC) for memory maintenance in mice performing an auditory WM task. Electrophysiological recordings revealed that AC neurons were active not only during the presentation of the auditory stimulus but also early in the delay period. Furthermore, optogenetic suppression of neural activity in AC during the stimulus epoch and early delay period impaired WM performance, whereas suppression later in the delay period did not. Thus, AC is essential for information encoding and maintenance in auditory WM task, especially during the early delay period.

Do noises wake you up at night? Blame your locus coeruleus.

Driving perception by direct activation of neural ensembles in cortex is a necessary step for achieving a causal understanding of the neural code for auditory perception and developing central sensory rehabilitation methods. Here, using optogenetic manipulations during an auditory discrimination task in mice, we show that auditory cortex can be short-circuited by coarser pathways for simple sound identification. Yet when the sensory decision becomes more complex, involving temporal integration of information, auditory cortex activity is required for sound discrimination and targeted activation of specific cortical ensembles changes perceptual decisions, as predicted by our readout of the cortical code. Hence, auditory cortex representations contribute to sound discriminations by refining decisions from parallel routes.

Threatening sounds can elicit a series of defensive behavioral reactions in animals for survival, but the underlying neural substrates are not fully understood. Here, we demonstrate a previously unexplored neural pathway in mice that projects directly from the auditory cortex (ACx) to the lateral periaqueductal gray (lPAG) and controls noise-evoked defensive behaviors. Electrophysiological recordings showed that the lPAG could be excited by a loud noise that induced an escape-like behavior. Trans-synaptic viral tracing showed that a great number of glutamatergic neurons, rather than GABAergic neurons, in the lPAG were directly innervated by those in layer V of the ACx. Activation of this pathway by optogenetic manipulations produced a behavior in mice that mimicked the noise-evoked escape, whereas inhibition of the pathway reduced this behavior. Therefore, our newly identified descending pathway is a novel neural substrate for noise-evoked escape and is involved in controlling the threat-related behavior.

Salience is a broad and widely used concept in neuroscience whose neuronal correlates, however, remain elusive. In behavioral conditioning, salience is used to explain various effects, such as stimulus overshadowing, and refers to how fast and strongly a stimulus can be associated with a conditioned event. Here, we identify sounds of equal intensity and perceptual detectability, which due to their spectro-temporal content recruit different levels of population activity in mouse auditory cortex. When using these sounds as cues in a Go/NoGo discrimination task, the degree of cortical recruitment matches the salience parameter of a reinforcement learning model used to analyze learning speed. We test an essential prediction of this model by training mice to discriminate light-sculpted optogenetic activity patterns in auditory cortex, and verify that cortical recruitment causally determines association or overshadowing of the stimulus components. This demonstrates that cortical recruitment underlies major aspects of stimulus salience during reinforcement learning.

A wealth of data has elucidated the mechanisms by which sensory inputs are encoded in the neocortex, but how these processes are regulated by the behavioral relevance of sensory information is less understood. Here, we focus on neocortical layer 1 (L1), a key location for processing of such top-down information. Using Neuron-Derived Neurotrophic Factor (NDNF) as a selective marker of L1 interneurons (INs) and in vivo 2-photon calcium imaging, electrophysiology, viral tracing, optogenetics, and associative memory, we find that L1 NDNF-INs mediate a prolonged form of inhibition in distal pyramidal neuron dendrites that correlates with the strength of the memory trace. Conversely, inhibition from Martinotti cells remains unchanged after conditioning but in turn tightly controls sensory responses in NDNF-INs. These results define a genetically addressable form of dendritic inhibition that is highly experience dependent and indicate that in addition to disinhibition, salient stimuli are encoded at elevated levels of distal dendritic inhibition. VIDEO ABSTRACT.