Hippocampal CA1 cells take part in reliable, time-locked activity sequences in tasks that involve an association between temporally separated stimuli, in a manner that tiles the interval between the stimuli. Such cells have been termed time cells. Here we adopt a first-principles approach to comparing diverse analysis and detection algorithms for identifying time cells. We generated synthetic activity datasets using calcium signals recorded in vivo from the mouse hippocampus using 2-Photon imaging, as template response waveforms. We assigned known, ground truth values to perturbations applied to perfect activity signals, including noise, calcium event width, timing imprecision, hit-trial ratio and background (untuned) activity. We tested a range of published and new algorithms and their variants on this dataset. We find that most algorithms correctly classify over 80% of cells, but have different balances between true and false positives, and different sensitivity to the five categories of perturbation. Re...

Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here we investigated a post-translational modification of CHTs – poly-ubiquitination - and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines measured in cortex and str...

Women are twice as likely as men to experience emotional dysregulation after stress, resulting in substantially higher psychopathology for equivalent lifetime stress exposure, yet mechanisms underlying this vulnerability remain unknown. Studies suggest changes in medial prefrontal cortex (mPFC) activity as a potential contributor. Whether maladaptive changes in inhibitory interneurons participate in this process, and whether adaptations in response to stress differ between men and women, producing sex-specific changes in emotional behaviors and mPFC activity, remained undetermined. This study examined whether unpredictable chronic mild stress (UCMS) in mice differentially alters behavior and mPFC parvalbumin (PV) interneuron activity by sex, and whether these neurons’ activity drives sex-specific behavioral changes. Four weeks of UCMS increased anxiety- and depressive-like behaviors associated with FosB activation in mPFC PV neurons, particularly in females. After 8 weeks of UCMS, both sexes displayed thes...

The cochlear nuclei (CN) receive sensory information from the ear and perform fundamental computations before relaying this information to higher processing centers. These computations are performed by distinct types of neurons interconnected in circuits dedicated to the specialized roles of the auditory system. In the present study we explored the use of voltage imaging to investigate CN circuitry. We tested two approaches based on fundamentally different voltage sensing technologies. Using a voltage-sensitive dye we recorded glutamate receptor-independent signals arising predominantly from axons. The mean conduction velocity of these fibers of 0.27 m/sec was rapid but in range with other unmyelinated axons. We then used a genetically-encoded hybrid voltage sensor (hVOS) to image voltage from a specific population of neurons. Probe expression was controlled using Cre recombinase linked to c-fos activation. This activity-induced gene enabled targeting of neurons that are activated when a mouse hears a pure...

Circadian photoperiod, or day length, changes with the seasons and influences behavior to allow animals to adapt to their environment. Photoperiod is also associated with seasonal rhythms of affective state, as evidenced by seasonality of several neuropsychiatric disorders. Interestingly, seasonality tends to be more prevalent in women for affective disorders such as Major Depressive Disorder and Bipolar Disorder. However, the underlying neurobiological processes contributing to sex-linked seasonality of affective behaviors are largely unknown. Mesolimbic dopamine input to the nucleus accumbens (NAc) contributes to the regulation of affective state and behaviors. Additionally, sex differences in the mesolimbic dopamine pathway are well-established. Therefore, we hypothesize that photoperiod may drive differential modulation of NAc dopamine in males and females. Here, we used fast-scan cyclic-voltammetry (FSCV) to explore whether photoperiod can modulate sub-second dopamine signaling dynamics in the NAc cor...

Voluntary movements are prepared before they are executed. Preparatory activity has been observed across the CNS and recently documented in first order neurons of the human PNS i.e., in muscle spindles. Changes seen in sensory organs suggest that independent modulation of stretch reflex gains may represent an important component of movement preparation. The aim of the current study was to further investigate the preparatory modulation of short- and long-latency stretch reflex responses ('SLR' and 'LLR') of the dominant upper limb of human subjects. Specifically, we investigated how different target parameters (target distance and direction) affect the preparatory tuning of stretch reflex gains in the context of goal-directed reaching, and whether any such tuning depends on preparation duration and the direction of background loads. We found that target distance produced only small variations in reflex gains. In contrast, both SLR and LLR gains were strongly modulated as a function of target direction, in a...

Hyperactivation of the mTOR signaling pathway is linked to more than a dozen neurological diseases, causing a range of pathologies, including excess neuronal growth, disrupted neuronal migration, cortical dysplasia, epilepsy and autism. The mTOR pathway also regulates angiogenesis. For the present study, therefore, we queried whether loss of Pten or Tsc2 , both mTOR negative regulators, alters brain vasculature in three mouse models: one with Pten loss restricted to hippocampal dentate granule cells (DGC- Pten KOs), a second with widespread Pten loss from excitatory forebrain neurons (FB- Pten KOs) and a third with focal loss of Tsc2 from cortical excitatory neurons (f- Tsc2 KOs). Total hippocampal vessel length and volume per dentate gyrus were dramatically increased in DGC- Pten knockouts. DGC- Pten knockouts had larger dentate gyri overall, however, and when normalized to these larger structures, vessel density was preserved. In addition, tests of blood-brain barrier integrity did not reveal increased p...

Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as post-traumatic stress disorder. Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP) 9 signalling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signalling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomised controlled trial ...

Nicotine robustly sustains smoking behavior by acting as a primer reinforcer and by enhancing the incentive salience of the nicotine associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood. In here we used a contingent nicotine and saline control self-administration model to disentangle the contribution of cue-elicited seeking responding for nicotine after drug abstinence in male Wistar rats. Using ex vivo electrophysiological recordings and a network analysis approach, we defined temporal and brain-region specific amygdalo-striatal glutamatergic alterations that occur during nicotine abstinence. The results from this study provide critical evidence indicating a persistent hypoglutamatergic state within the amygdalo-striatal...

Facial expressions are an increasingly utilized tool to assess emotional experience and affective state during experimental procedures in animal models. Previous studies have successfully related specific facial features with different positive and negative valence situations, most notably in relation to pain. However, characterizing and interpreting such expressions remains a major challenge. We identified seven easily visualizable facial parameters on mouse profiles, accounting for changes in eye, ear, mouth, snout and face orientation. We monitored their relative position on the face across time and throughout sequences of positive and aversive gustatory and somatosensory stimuli in freely moving mice. Facial parameters successfully captured response profiles to each stimulus and reflected spontaneous movements in response to stimulus valence, as well as contextual elements such as habituation. Notably, eye opening was increased by palatable tastants and innocuous touch, while this parameter was reduced...