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The dentate gyrus is critical for spatial memory formation and shows task-related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype, were reported to be enriched among behaviorally activated neurons. By examining SGCs and granule cells (GCs) labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. Consistent with more excitable neurons being recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, labeled SGCs showed less adapting firing than unlabeled SGCs. The lack of glutamatergic connections between behaviorally labeled SGCs and GCs in our recordings is inconsistent with SGC-driven local circuit feedforward excitation underlying ensemble recruitment. Moreover, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, labeled GCs and SGCs received more spontaneous excitatory synaptic inputs than their unlabeled counterparts. Labeled neuronal pairs received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic excitability and correlated inputs in preferential SGC recruitment to contextual memory engrams.

The dentate gyrus is critical for spatial memory formation and shows task-related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype, were reported to be enriched among behaviorally activated neurons. By examining SGCs and granule cells (GCs) labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. Consistent with more excitable neurons being recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, labeled SGCs showed less adapting firing than unlabeled SGCs. The lack of glutamatergic connections between behaviorally labeled SGCs and GCs in our recordings is inconsistent with SGC-driven local circuit feedforward excitation underlying ensemble recruitment. Moreover, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, labeled GCs and SGCs received more spontaneous excitatory synaptic inputs than their unlabeled counterparts. Labeled neuronal pairs received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic excitability and correlated inputs in preferential SGC recruitment to contextual memory engrams.

Strategies for optimized performance in any task do not spontaneously occur. They develop over time. Across learning, our first strategy may be a successful strategy. On the other hand, we may require multiple strategies to succeed in a task. In this body of work, we examine spatial and temporal behavioral and neuronal strategies relevant to reward driven decision making using a whisker-based selective detection paradigm where mice learn to selectively respond to a preferred (target) stimulus and selectively ignore a nonpreferred (distractor) stimulus. Through widefield calcium imaging of task-relevant sensory and motor cortices, we first identified comparable target and distractor stimulus encoding in sensory regions, followed by attenuation of distractor and propagation of target encoding in motor regions. We interpret this localized attenuation filter as a functional, potentially reactive, neural strategy for the selection process after stimulus presentation and before a planned motor response. Then we found that a global cortical state of low activity and low variability in a prestimulus epoch predicted response outcomes. We interpret the global prestimulus profile as a preemptive, potentially proactive, neural strategy before stimulus presentation. Finally, longitudinal investigation across learning behavior revealed that mice used both object-based and temporal strategies to transition from naïve to expert performance in the selective detection task. Furthermore, we found that the transition strategies differed between male and female mice such that male mice overlapped their response and temporal strategies before improving their object-based performance and that female mice improved their performance through sequential temporal and object-based intermediate strategies. We find evidence that supports development of multiple strategies across learning, transitioning mice from suboptimal to optimal performance in the selective detection task. In conjunction with the neural findings of expert behaving mice, we can further our understanding of how behavioral strategies form across learning to maximize successful outcomes.

The dentate gyrus is critical for spatial memory formation and shows task related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype distinct from granule cells (GCs), were recently reported to be enriched among behaviorally activated neurons. However, the mechanisms governing SGC recruitment during memory formation and their role in engram refinement remains unresolved. By examining neurons labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. In support of the proposal that more excitable neurons are preferentially recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, SGCs labeled during memory formation showed less adapting firing than unlabeled SGCs. Our recordings did not reveal glutamatergic connections between behaviorally labeled SGCs and GCs, providing evidence against SGC driven local circuit feedforward excitation in ensemble recruitment. Contrary to a leading hypothesis, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, labeled GCs and SGCs received more spontaneous excitatory synaptic inputs than their unlabeled counterparts. Moreover, pairs of GCs and SGCs within labeled neuronal cohorts received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs, validating a role for correlated afferent inputs in neuronal ensemble selection. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic active properties and correlated inputs in preferential SGC recruitment to contextual memory engrams.

New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naïve to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus-response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of licking-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.

Goal-directed behavior paradigms inevitably involve temporal processes, such as anticipation, expectation, timing, waiting, and withholding. And yet, amongst the vast use of object-based task paradigms, characterizations of temporal features are often neglected. Here, we longitudinally analyzed mice from naive to expert performance in a somatosensory selective detection task. In addition to tracking standard measures from signal detection theory, we also characterized learning of temporal features. We find that mice transition from general sampling strategies to stimulus detection and stimulus discrimination. During these transitions, mice learn to wait as they anticipate an expected stimulus presentation and to time their response after a stimulus presentation. By establishing and implementing standardized measures, we show that the development of waiting and timing in the task overlaps with learning of stimulus detection and discrimination. We also investigated sex differences in temporal and object-based trajectories of learning, finding that males learn strategies idiosyncratically and that females learn strategies more sequentially and stereotypically. Overall, our findings emphasize multiple temporal strategies in learning for an object-based task and highlight the importance of considering diverse temporal and object-based features when characterizing behavioral and neuronal aspects of learning.Competing Interest StatementThe authors have declared no competing interest.

Spontaneous neuronal activity strongly impacts stimulus encoding and behavioral responses. We sought to determine the effects of neocortical prestimulus activity on stimulus detection. We trained mice in a selective whisker detection task, in which they learned to respond (lick) to target stimuli in one whisker field and ignore distractor stimuli in the contralateral whisker field. During expert task performance, we used widefield Ca2+ imaging to assess prestimulus and post-stimulus neuronal activity broadly across frontal and parietal cortices. We found that lower prestimulus activity correlated with enhanced stimulus detection: lower prestimulus activity predicted response versus no response outcomes and faster reaction times. The activity predictive of trial outcome was distributed through dorsal neocortex, rather than being restricted to whisker or licking regions. Using principal component analysis, we demonstrate that response trials are associated with a distinct and less variable prestimulus neuronal subspace. For single units, prestimulus choice probability was weak yet distributed broadly, with lower than chance choice probability correlating with stronger sensory and motor encoding. These findings support a low amplitude, low variability, optimal prestimulus cortical state for stimulus detection that presents globally and predicts response outcomes for both target and distractor stimuli. Competing Interest Statement The authors have declared no competing interest.

An essential feature of goal-directed behavior is the ability to selectively respond to the diverse stimuli in one's environment. However, the neural mechanisms that enable us to respond to target stimuli while ignoring distractor stimuli are poorly understood. To study this sensory selection process, we trained male and female mice in a selective detection task in which mice learn to respond to rapid stimuli in the target whisker field and ignore identical stimuli in the opposite, distractor whisker field. In expert mice, we used widefield Ca2+ imaging to analyze target-related and distractor-related neural responses throughout dorsal cortex. For target stimuli, we observed strong signal activation in primary somatosensory cortex (S1) and frontal cortices, including both the whisker representation of primary motor cortex (wMC) and anterior lateral motor cortex (ALM). For distractor stimuli, we observe strong signal activation in S1, with minimal propagation to frontal cortex. Our data support only modest subcortical filtering, with robust, step-like attenuation in distractor processing between mono-synaptically coupled regions of S1 and wMC. This study establishes a highly robust model system for studying the neural mechanisms of sensory selection and places important constraints on its implementation.