Pavlovian conditioning tasks have been used to identify the neural systems involved with learning cue–outcome relationships. In delay conditioning, the conditioned stimulus (CS) overlaps or co-terminates with the unconditioned stimulus (US). Prior studies demonstrate that dopamine in the nucleus accumbens (NAc) regulates behavioral responding during delay conditioning. Furthermore, the dopamine response to the CS reflects the relative value of the upcoming reward in these tasks. In contrast to delay conditioning, trace conditioning involves a “trace” period separating the end of the CS and the US delivery. While dopamine has been implicated in trace conditioning, no studies have examined how NAc dopamine responds to reward-related stimuli in these tasks. Here, we developed a within-subject trace conditioning task where distinct CSs signaled either a short trace period (5 s) or a long trace period (55 s) prior to food reward delivery. Male rats exhibited greater conditioned responding and a faster response ...

Histone deacetylase 3 (HDAC3) is one of the most highly expressed HDACs in the brain shown to be a negative regulator of long-term memory formation. HDAC3 has also been shown to be involved in cocaine-associated behaviors, demonstrated by manipulations in the nucleus accumbens. Previous studies have demonstrated that expression of a dominant negative of a key HDAC3 target gene, nuclear receptor subfamily 4 group A member 2 (NR4A2), in cholinergic neurons of the medial habenula (MHb) blocked reinstatement of cocaine-induced conditioned place preference (CPP) as well as cue-induced intravenous self-administration (IVSA). Together, these findings suggested that HDAC3 would also be important for MHb-dependent reinstatement of CPP and IVSA, which we examined in this study. Contrary to our hypothesis, our results found that expression of an HDAC3 deacetylase dead point mutant within the cholinergic neurons of the mouse MHb had no effect on reinstatement or other cocaine-induced behaviors.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method that has been used to treat various brain disorders. The modulatory effects of rTMS can be adjusted by changing the repetition patterns. Theta-burst magnetic stimulation (TBS) is a magnetic stimulation pattern that can induce long-lasting modulatory effects with a short stimulation period. However, its effects on auditory brain regions remain unclear because of a lack of animal studies in which invasive techniques allow for a detailed exploration of the underlying neural mechanisms. In the current study, we investigated the effects of TBS on the C57BL/6J mouse auditory cortex using a custom-built 7 mm magnetic stimulation coil. Extracellular recordings were made before, during, and after the application of intermittent TBS (iTBS), continuous TBS (cTBS), or sham stimulation. Local field potential amplitudes were increased for 5–20 min post-iTBS compared with the sham condition and were decreased at 10 min post-cTBS compared with the...

The explore/exploit trade-off is a fundamental property of choice selection during reward-guided decision making, where the “same” choice can reflect either of these internal cognitive states. An unanswered question is whether the execution of a decision provides an underexplored measure of internal cognitive states. Touchscreens are increasingly used across species for cognitive testing and afford the ability to measure the precise location of choice touch responses. We examined how male and female mice in a restless bandit decision making task interacted with a touchscreen to determine if the explore/exploit trade-off, prior reward, and/or sex differences change the variability in the kinetics of touchscreen choices. During exploit states, successive touch responses are closer together than those made in an explore state, suggesting exploit states reflect periods of increased motor stereotypy. Although exploit decisions might be expected to be rewarded more frequently than explore decisions, we find that...

Recording the spiking activity from subcellular compartments of neurons such as axons and dendrites during mouse behavior with 2-photon calcium imaging is increasingly common yet remains challenging due to low signal-to-noise, inaccurate region-of-interest (ROI) identification, movement artifacts, and difficulty in grouping ROIs from the same neuron. To address these issues, we present a computationally efficient preprocessing pipeline for subcellular signal detection, movement artifact identification, and ROI grouping. For subcellular signal detection, we capture the frequency profile of calcium transient dynamics by applying fast Fourier transform (FFT) on smoothed time-series calcium traces collected from axon ROIs. We then apply bandpass filtering methods (e.g., 0.05–0.12 Hz) to select ROIs that contain frequencies that match the power band of transients. To remove motion artifacts from z -plane movement, we apply principal component analysis on all calcium traces and use a bottom-up segmentation chang...

In the Syngap+/− model of SYNGAP1-related intellectual disability (SRID), excessive neuronal protein synthesis is linked to deficits in synaptic plasticity. Here, we use Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) to identify mistranslating mRNAs in Syngap+/− CA1 pyramidal neurons that exhibit occluded long-term potentiation (LTP). We find the translation environment is significantly altered in a manner that is distinct from the Fmr1−/y model of fragile X syndrome (FXS), another monogenic model of autism and intellectual disability. The Syngap+/− translatome is enriched for regulators of DNA repair and mimics changes induced with chemical LTP (cLTP) in WT. This includes a striking upregulation in the translation of mRNAs with a longer-length (>2 kb) coding sequence (CDS). In contrast, long CDS transcripts are downregulated with induction of Gp1 metabotropic glutamate receptor-induced long-term depression (mGluR-LTD) in WT, and in the Fmr1−/y model that exhibits occluded mGluR-LTD. Tog...

Sleep consists of two alternating states—rapid eye movement (REM) and non-REM (NREM) sleep. Neurons adjust their firing activity based on brain state, however, the extent to which this modulation varies across neurons and brain regions remains poorly understood. This study analyzed previously acquired 17-h continuous recordings of single-unit activity and local field potentials in the ventral hippocampal CA1 region, prelimbic cortex layer 5, and basolateral nucleus of the amygdala of fear-conditioned rats. The findings indicate that more than half of the neurons fired faster during REM sleep than during NREM sleep, although a notable subset of neurons exhibited the opposite preference, firing preferentially during NREM sleep. During sleep, the overall firing activity of both REM- and NREM-preferring neurons decreased. However, fast network oscillations, including hippocampal sharp-wave ripples (SWRs), amygdalar high-frequency oscillations, cortical ripples, and cortical spindles, differentially modulated R...

Principal neurons (PNs) of the lateral superior olive (LSO) are a critical component of brain circuits that compare information between the two ears to extract sound source-location-related cues. LSO PNs are not a homogenous group but differ in their transmitter type, intrinsic membrane properties, and projection pattern to higher processing centers in the inferior colliculus. Glycinergic inhibitory LSO PNs have higher input resistance than glutamatergic excitatory LSO PNs (∼double). This suggests that the inhibitory cell type has a lower minimum input or signal intensity required to produce an output (activation threshold) which may impact how they integrate binaural inputs. However, cell-type-specific differences in the strength of synaptic drive could offset or accentuate such differences in intrinsic excitability and have not been assessed. To evaluate this possibility, we used a knock-in mouse model to examine spontaneous and electrically stimulated (evoked) synaptic events in LSO PN types using volta...

Activation of hypothalamic paraventricular oxytocin (OXTPVN) neurons by social or stress stimuli triggers OXT release to promote social investigation and buffer adverse effects of stress, respectively. Astrocytes, a type of glial cells, can bidirectionally interact with hypothalamic neurons to participate in local activity regulation within the paraventricular nucleus (PVN). It remains unknown whether contextual factors related to stimuli, as well as biological factors such as sex, influence OXTPVN neuronal or astrocyte activity and/or their interactions. To address this question, we performed dual-color fiber photometry in freely behaving male and female mice to simultaneously record Ca2+ dynamics in OXTPVN neurons and astrocytes during acute social (i.e., interactions with familiar vs. unfamiliar conspecifics) and stress (i.e., looming shadow) stimuli. During social stimuli, we observed the most pronounced Ca2+ changes in OXTPVN neurons in females, revealing sex and familiarity context specificity. No as...

Temporal lobe epilepsy (TLE) is a devastating disease, often pharmacoresistant and with a high prevalence of 1% worldwide. There are a few disease-modifying therapies; thus, prevention has become a health priority. The overarching goal of this research project is to highlight the system's dynamics at different stages before TLE onset to identify an early shift in network dynamics trajectory toward disease onset. Researchers often investigate collective brain activity by tracking dynamical interactions of the signal recorded at multiple sites. However, these interactions are usually only computed between pairs of brain regions, at the risk of missing simultaneous interactions of three or more areas, an aspect that is crucial in a networked disease such as TLE. We thus propose to track, on a rich dataset of electrophysiological brain signals recorded within the temporal lobe (TL) of adult male Wistar Han rats, the formation and dissolution of high-order informational multiplets in time during distinct natura...