Attending and presenting my research on fear behavior in rodents at Neuroscience 2022 was a significant experience that challenged prevailing beliefs in the field.

Felix Felmy and Nikolaos Kladisios discuss their paper, “Synaptic Mechanisms underlying Temporally Precise Information Processing in the VNLL, an auditory brainstem nucleus”, published in Vol. 42, Issue 34 of JNeurosci, with Reviewing Editor Ruth Anne Eatock. 

Dopaminergic inputs to various brain regions, such as the striatum, orbitofrontal cortex, and amygdala play a critical role in processing reward acquisition information. While reward-related activity is also observed more broadly in motor, parietal, and hippocampal regions, the functional significance and potential hierarchy of reward-related representation across these latter areas remain unclear. We investigated this by quantifying neural predictive power using machine learning. Specifically, neural activity was examined in six brain areas—the primary and secondary motor cortices (M1 and M2), posterior parietal cortex (PPC), dorsal and ventral CA1 (dCA1 and vCA1), and lateral entorhinal cortex (LEC)—in male rats performing a self-initiated left-right choice task. Machine learning models classified rewarded versus non-rewarded trials based on neuronal firing properties significantly above chance for all regions. Crucially, classification revealed a clear performance gradient, forming a functional hierarch...

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Neurexins (Nrxns) are presynaptic cell adhesion molecules essential for synapse development and function. Of the many neurexin isoforms, only β-Nrxns contain the histidine-rich domain (HRD). While the HRD has been implicated in several pathological contexts, its normal physiological role remains unclear. To address this, we used a CRISPR-Cas9 method to generate a new mouse line expressing in-frame truncated Nrxn1β lacking the HRD. We found that HRD deletion did not affect mouse viability, gross brain development, or general behavior of either sex. However, loss of the HRD significantly altered neuroligin-1-dependent excitatory, but not inhibitory, presynaptic differentiation in primary cultured neurons. Moreover, this deletion affected presynaptic short-term plasticity, but not basal synaptic transmission, at hippocampal Schaffer collateral-CA1 synapses. These findings identify the Nrxn1β HRD as a potential contributor to excitatory presynaptic organization and function, providing new insight into the mole...

Leila Reddy discusses her paper, “Human Hippocampal Neurons Track Moments in a Sequence of Events,” published in Vol. 41, Issue 31 of The Journal of Neuroscience, with Editor-in-Chief Marina Picciotto. 

The cerebellum is well-established in sub-second motor timing, but its role in supra-second interval timing remains unclear. Here, we investigated how cerebellar output influences time estimation over longer timescales. Male rats performed a nose-poke interval timing task in which reward availability could be predicted either from a fixed 2.5 s auditory cue (cued trials) or had to be estimated internally during uncued 3.5 s trials that demanded self-timing. Chemogenetic inhibition of the lateral cerebellar nucleus produced bidirectional effects: delayed action initiation in predictable trials and premature (∼100-160 ms) responses when self-timing was required. Despite a slowing of movement, overall task success rates remained unchanged. Because motor slowing is likely to lead to later, not earlier, action initiation, these results implicate the lateral cerebellar nucleus in computing internal time estimates. These findings demonstrate that the cerebellum integrates motor and cognitive processes for supra-s...

Investigations into the neural basis of behavior frequently employ calcium imaging to measure neuronal activity. Across studies, however, seemingly reasonable but highly diverse methodological choices are typically made to assess the selectivity of individual neurons to task states. Here, we examine systematically the effect of parameter choices, along the pipeline from data acquisition through statistical testing, on the inferred encoding preferences of individual neurons. We use as an experimental testbed, calcium imaging in the medial prefrontal cortex of freely behaving mice engaged in a classic exploration-avoidance task with animal-controlled state transitions, namely, navigation in the elevated zero maze. We report that most of the key parameters in the pipeline substantially impact the inferred selectivity of neurons, and do so in distinct ways. Using novel accuracy and robustness metrics, we directly compare the quality of inference across combinations of parameter levels, and discover an optimal ...

Gamma oscillations (40-140 Hz) play a fundamental role in neural coordination and cognitive functions in the medial entorhinal cortex (mEC). While previous studies suggest that pyramidal-interneuron network gamma (PING) and interneuron network gamma (ING) mechanisms contribute to these oscillations, the precise role of inhibitory circuits remains unclear. Using optogenetic stimulation and whole-cell electrophysiology in acute mouse brain slices, we examined synaptic input and spike timing in neurons across layer II/III mEC. We found that fast-spiking interneurons exhibited robust gamma-frequency firing, while excitatory neurons engaged in gamma cycle skipping. Stellate and pyramidal cells received minimal recurrent excitation, whereas fast-spiking interneurons received strong excitatory input. Both excitatory neurons and fast-spiking interneurons received gamma frequency inhibition, emphasizing the role of recurrent inhibition in gamma rhythms. Gamma activity was reduced, but persisted after AMPA/kainate r...

The dorsomedial striatum (DMS) is critical for both motivating and inhibiting behavioral responses. The region integrates inputs from the cortex, thalamus, and other subcortical structures including midbrain dopamine neurons. Though less studied, serotonin neurons from the dorsal raphe nucleus also richly innervate the DMS, which expresses nearly all 14 serotonin receptor subtypes. Slice electrophysiology shows that the serotonin 1B receptor (5-HT1BR) impacts DMS physiology and plasticity, and behavioral experiments show that 5-HT1BR expression modulates impulsivity and other DMS-dependent reward-related behaviors. In these studies, our goal was to investigate the effects of 5-HT1BR on the DMS in vivo. Using a genetic 5-HT1BR loss-of-function mouse model, we examined the calcium activity of individual medium spiny neurons (MSNs) in the DMS of both males and females during operant tasks focusing on the response to actions, reward, and waiting. We found that knockout of 5-HT1BRs resulted in different effects...