Shantanu P. Jadhav

Somatosensory Integration Controlled by Dynamic Thalamocortical Feed-Forward Inhibition

The temporal features of tactile stimuli are faithfully represented by the activity of neurons in the somatosensory cortex. However, the cellular mechanisms that enable cortical neurons to report accurate temporal information are not known. Here, we show that in the rodent barrel cortex, the temporal window for integration of thalamic inputs is under the control of thalamocortical feed-forward inhibition and can vary from 1 to 10 ms. A single thalamic fiber can trigger feed-forward inhibition and contacts both excitatory and inhibitory cortical neurons. The dynamics of feed-forward inhibition exceed those of each individual synapse in the circuit and are captured by a simple disynaptic model of the thalamocortical projection. The variations in the integration window produce changes in the temporal precision of cortical responses to whisker stimulation. Hence, feed-forward inhibitory circuits, classically known to sharpen spatial contrast of tactile inputs, also increase the temporal resolution in the somatosensory cortex.

Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval

The hippocampus is required for the encoding, consolidation and retrieval of event memories. Although the neural mechanisms that underlie these processes are only partially understood, a series of recent papers point to awake memory replay as a potential contributor to both consolidation and retrieval. Replay is the sequential reactivation of hippocampal place cells that represent previously experienced behavioral trajectories and occurs frequently in the awake state, particularly during periods of relative immobility. Awake replay may reflect trajectories through either the current environment or previously visited environments that are spatially remote. The repetition of learned sequences on a compressed time scale is well suited to promote memory consolidation in distributed circuits beyond the hippocampus, suggesting that consolidation occurs in both the awake and sleeping animal. Moreover, sensory information can influence the content of awake replay, suggesting a role for awake replay in memory retrieval.

Awake Hippocampal Sharp-Wave Ripples Support Spatial Memory

Spatial Memory Perturbation The hippocampus is important for learning and memory. However, it is not clear which patterns of neural activity in the hippocampus support specific mnemonic functions. Jadhav et al. (p. 1454, published online 3 May) developed a real-time analysis system to detect and selectively interrupt a certain type of hippocampal neuronal network event—sharp-wave ripples—during learning. In awake animals, loss of sharp-wave ripples and associated memory replay activity caused a learning deficit specific to spatial working memory but had no effect on reference memory. This learning deficit was present despite the preservation of place-field representations and replay activity during rest. The neuronal “replay” of past experience may allow animals to retrieve specific memories and use them to guide behavior. The hippocampus is critical for spatial learning and memory. Hippocampal neurons in awake animals exhibit place field activity that encodes current location, as well as sharp-wave ripple (SWR) activity during which representations based on past experiences are often replayed. The relationship between these patterns of activity and the memory functions of the hippocampus is poorly understood. We interrupted awake SWRs in animals learning a spatial alternation task. We observed a specific learning and performance deficit that persisted throughout training. This deficit was associated with awake SWR activity, as SWR interruption left place field activity and post-experience SWR reactivation intact. These results provide a link between awake SWRs and hippocampal memory processes, which suggests that awake replay of memory-related information during SWRs supports learning and memory-guided decision-making.

PROLONGED BEHAVIORAL STRESS ENHANCES SYNAPTIC CONNECTIVITY IN THE BASOLATERAL AMYGDALA

Recently identified cellular and molecular correlates of stress-induced plasticity suggest a putative link between neuronal remodeling in the amygdala and the development of anxiety-like behavior. Rodent models of immobilization stress, applied for 10 consecutive days, have been reported to enhance anxiety, and also cause dendritic elongation and spine formation in the basolateral amygdala (BLA). Paradoxically, longer exposure to stress, which is also anxiogenic, fails to affect key molecular markers of neuronal remodeling in the BLA. This has raised the possibility of homeostatic mechanisms being triggered by more prolonged stress that could potentially dampen the morphological effects of stress in the BLA. Therefore, we examined the cellular and behavioral impact of increasing the duration of stress in rats. We find that prolonged immobilization stress (PIS), spanning 21 days, caused significant enhancement in dendritic arborization of spiny BLA neurons. Spine density was also enhanced along these elongated dendrites in response to PIS. Finally, this striking increase in synaptic connectivity was accompanied by enhanced anxiety-like behavior in the elevated plus-maze. Thus, we did not detect any obvious morphological correlate of adaptive changes within the BLA that may have been activated by prolonged and repeated application of the same stressor for 21 days. These findings add to accumulating evidence that structural encoding of aversive experiences, through enhanced availability of postsynaptic dendritic surface and synaptic inputs on principal neurons of the BLA, may contribute to the affective symptoms of stress disorders.

Sparse temporal coding of elementary tactile features during active whisker sensation

How the brain encodes relevant sensory stimuli in the context of active, natural sensation is not known. During active tactile sensation by rodents, whisker movement across surfaces generates complex whisker micro-motion, including discrete, transient slip-stick events, which carry information about surface properties. We simultaneously measured whisker motion and neural activity in somatosensory cortex (S1) in rats whisking across surfaces. Slip-stick motion events were prominently encoded by one or two low-probability, precisely timed spikes in S1 neurons, resulting in a probabilistically sparse ensemble code. Slips could be efficiently decoded from transient, correlated spiking (∼20-ms time scale) in small (∼100 neuron) populations. Slip responses contributed substantially to increased firing rate and transient firing synchrony on surfaces, and firing synchrony was an important cue for surface texture. Slips are thus a fundamental encoded tactile feature in natural whisker input streams and are represented by sparse, temporally precise, synchronous spiking in S1.

Texture coding in the whisker system

The whisker somatosensory system in awake, behaving rodents is a powerful model for studying neurobiology of sensation, from molecules to circuits to behavior. Recent studies reveal how key tactile features are detected in awake animals and encoded by spike trains in somatosensory cortex (S1). Here we summarize progress on detection of surface texture (roughness). Texture appears to be inferred from the statistics of complex, irregular whisker micromotion on surfaces, specifically by mean speed or by patterns of discrete, high-velocity whisker slips. These are encoded in S1 by mean firing rate and by sparse, synchronous, slip-evoked spike volleys, respectively. An alternative model of place coding for texture based on differential whisker resonance is less well supported, but is not ruled out.

Endocannabinoid signaling is required for development and critical period plasticity of the whisker map in somatosensory cortex.

Type 1 cannabinoid (CB1) receptors mediate widespread synaptic plasticity, but how this contributes to systems-level plasticity and development in vivo is unclear. We tested whether CB1 signaling is required for development and plasticity of the whisker map in rat somatosensory cortex. Treatment with the CB1 antagonist AM251 during an early critical period for layer (L) 2/3 development (beginning postnatal day [P] 12-16) disrupted whisker map development, leading to inappropriate whisker tuning in L2/3 column edges and a blurred map. Early AM251 treatment also prevented experience-dependent plasticity in L2/3, including deprivation-induced synapse weakening and weakening of deprived whisker responses. CB1 blockade after P25 did not disrupt map development or plasticity. AM251 had no acute effect on sensory-evoked spiking and only modestly affected field potentials, suggesting that plasticity effects were not secondary to gross activity changes. These findings implicate CB1-dependent plasticity in systems-level development and early postnatal plasticity of the whisker map.

Coordinated Excitation and Inhibition of Prefrontal Ensembles during Awake Hippocampal Sharp-Wave Ripple Events

Interactions between the hippocampus and prefrontal cortex (PFC) are critical for learning and memory. Hippocampal activity during awake sharp-wave ripple (SWR) events is important for spatial learning, and hippocampal SWR activity often represents past or potential future experiences. Whether or how this reactivation engages the PFC, and how reactivation might interact with ongoing patterns of PFC activity, remains unclear. We recorded hippocampal CA1 and PFC activity in animals learning spatial tasks and found that many PFC cells showed spiking modulation during SWRs. Unlike in CA1, SWR-related activity in PFC comprised both excitation and inhibition of distinct populations. Within individual SWRs, excitation activated PFC cells with representations related to the concurrently reactivated hippocampal representation, while inhibition suppressed PFC cells with unrelated representations. Thus, awake SWRs mark times of strong coordination between hippocampus and PFC that reflects structured reactivation of representations related to ongoing experience.

Psychometric Curve and Behavioral Strategies for Whisker-Based Texture Discrimination in Rats

The rodent whisker system is a major model for understanding neural mechanisms for tactile sensation of surface texture (roughness). Rats discriminate surface texture using the whiskers, and several theories exist for how texture information is physically sensed by the long, moveable macrovibrissae and encoded in spiking of neurons in somatosensory cortex. However, evaluating these theories requires a psychometric curve for texture discrimination, which is lacking. Here we trained rats to discriminate rough vs. fine sandpapers and grooved vs. smooth surfaces. Rats intermixed trials at macrovibrissa contact distance (nose >2 mm from surface) with trials at shorter distance (nose <2 mm from surface). Macrovibrissae were required for distant contact trials, while microvibrissae and non-whisker tactile cues were used for short distance trials. A psychometric curve was measured for macrovibrissa-based sandpaper texture discrimination. Rats discriminated rough P150 from smoother P180, P280, and P400 sandpaper (100, 82, 52, and 35 µm mean grit size, respectively). Use of olfactory, visual, and auditory cues was ruled out. This is the highest reported resolution for rodent texture discrimination, and constrains models of neural coding of texture information.

Interplay between Hippocampal Sharp-Wave-Ripple Events and Vicarious Trial and Error Behaviors in Decision Making

Current theories posit that memories encoded during experiences are subsequently consolidated into longer-term storage. Hippocampal sharp-wave-ripple (SWR) events have been linked to this consolidation process during sleep, but SWRs also occur during awake immobility, where their role remains unclear. We report that awake SWR rates at the reward site are inversely related to the prevalence of vicarious trial and error (VTE) behaviors, thought to be involved in deliberation processes. SWR rates were diminished immediately after VTE behaviors and an increase in the rate of SWR events at the reward site predicted a decrease in subsequent VTE behaviors at the choice point. Furthermore, SWR disruptions increased VTE behaviors. These results suggest an inverse relationship between SWRs and VTE behaviors and suggest that awake SWRs and associated planning and memory consolidation mechanisms are engaged specifically in the context of higher levels of behavioral certainty.