The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been associated with the expression of adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, reported effects of mPFC manipulations on cue-elicited natural reward-seeking and inhibition thereof have been varied, with few studies examining cortico-striatal contributions in tasks that require adaptive responding to cues signaling reward and punishment within the same session. The current study aimed to better elucidate the role of mPFC and NAc subdivisions, and their functional connectivity in cue-elicited adaptive responding using a novel discriminative cue responding task. Male Long–Evans rats learned to lever-press on a VR5 schedule for a discriminative cue signaling reward, and to avoid pressing the same lever in the presence of another cue signaling punishment. Postacquisition, prelimbic (PL) and infralimbic (IL) areas of the mPFC, NAc core, shell, PL-core, or IL-shell circuits were pharmacologic...

Recent branching (100 MYA) of the mammalian evolutionary tree has enhanced brain complexity and functions at the putative cost of increased emotional circuitry vulnerability. Thus, to better understand psychopathology, a burden for the modern society, novel approaches should exploit evolutionary aspects of psychiatric-relevant molecular pathways. A handful of genes is nowadays tightly associated to psychiatric disorders. Among them, neuronal-enriched RbFOX1 modifies the activity of synaptic regulators in response to neuronal activity, keeping excitability within healthy domains. We here dissect a higher primates-restricted interaction between RbFOX1 and the transcriptional corepressor Lysine Specific Demethylase 1 (LSD1/KDM1A). A single nucleotide variation (AA to AG) in LSD1 gene appeared in higher primates and humans, endowing RbFOX1 with the ability to promote the alternative usage of a novel 3′ AG splice site, which extends LSD1 exon E9 in the upstream intron (E9-long). Exon E9-long regulates LSD1 leve...

Humans have the ability to store and retrieve memories with various degrees of specificity, and recent advances in reinforcement learning have identified benefits to learning when past experience is represented at different levels of temporal abstraction. How this flexibility might be implemented in the brain remains unclear. We analyzed the temporal organization of male rat hippocampal population spiking to identify potential substrates for temporally flexible representations. We examined activity both during locomotion and during memory-associated population events known as sharp-wave ripples (SWRs). We found that spiking during SWRs is rhythmically organized with higher event-to-event variability than spiking during locomotion-associated population events. Decoding analyses using clusterless methods further indicate that a similar spatial experience can be replayed in multiple SWRs, each time with a different rhythmic structure whose periodicity is sampled from a log-normal distribution. This variabilit...

Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially tuned, temporally diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats in vitro (slice electrophysiology) and in silico (multicompartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared with somatic ramps. We incorporated a four-state Markov scheme for NaV1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to expl...

Sleep is a universally conserved physiological state which contributes toward basic organismal functions, including cognitive operations such as learning and memory. Intriguingly, organisms can sometimes form memory even without sleep, such that Drosophila display sleep-dependent and sleep-independent memory in an olfactory appetitive training paradigm. Sleep-dependent memory can be elicited by the perception of sweet taste, and we now show that a mixed-sex population of flies maintained on sorbitol, a tasteless but nutritive substance, do not require sleep for memory consolidation. Consistent with this, silencing sugar-sensing gustatory receptor neurons in fed flies triggers a switch to sleep-independent memory consolidation, whereas activating sugar-sensing gustatory receptor neurons results in the formation of sleep-dependent memory in starved flies. Sleep-dependent and sleep-independent memory relies on distinct subsets of reward signaling protocerebral anterior medial dopaminergic neurons (PAM DANs) s...

Due to their ex utero development, relatively simple nervous system, translucency, and availability of tools to investigate neural function, larval zebrafish are an exceptional model for understanding neurodevelopmental disorders and the consequences of environmental toxins. Furthermore, early in development, zebrafish larvae easily absorb chemicals from water, a significant advantage over methods required to expose developing organisms to chemical agents in utero . Bisphenol A (BPA) and BPA analogs are ubiquitous environmental toxins with known molecular consequences. All humans have measurable quantities of BPA in their bodies. Most concerning, the level of BPA exposure is correlated with neurodevelopmental difficulties in people. Given the importance of understanding the health-related effects of this common toxin, we have exploited the experimental advantages of the larval zebrafish model system to investigate the behavioral and anatomical effects of BPA exposure. We discovered that BPA exposure early ...

Although there is mounting evidence that input from the dorsal visual pathway is crucial for object processes in the ventral pathway, the specific functional contributions of dorsal cortex to these processes remain poorly understood. Here, we hypothesized that dorsal cortex computes the spatial relations among an object’s parts – a processes crucial for forming global shape percepts – and transmits this information to the ventral pathway to support object categorization. Using fMRI with human participants (females and males), we discovered regions in the intraparietal sulcus (IPS) that were selectively involved in computing object-centered part relations. These regions exhibited task-dependent functional and effective connectivity with ventral cortex, and were distinct from other dorsal regions, such as those representing allocentric relations, 3D shape, and tools. In a subsequent experiment, we found that the multivariate response of posterior IPS, defined on the basis of part-relations, could be used to ...

Electrocorticography (ECoG) methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. To address this gap, we recorded from rat auditory cortex using customized μECoG, and simulated cortical surface electrical potentials with a full-scale, biophysically detailed cortical column model. Experimentally, μECoG-derived auditory representations were tonotopically organized and signals were anisotropically localized to less than or equal to ±200 μm, that is, a single cortical column. Biophysical simulations reproduce experimental findings and indicate that neurons in cortical layers V and VI contribute ∼85% of evoked high-gamma signal recorded at the surface. Cell number and synchrony were the primary biophysical properties determining laminar contributions to evoked μECoG signals, whereas distance was only a m...

To successfully forage in an environment filled with rewards and threats, animals need to rely on familiar structures of their environment that signal food availability. The central amygdala (CeA) is known to mediate a panoply of consummatory and defensive behaviors, yet how specific activity patterns within CeA subpopulations guide optimal choices is not completely understood. In a paradigm of appetitive conditioning in which mice freely forage for food across a continuum of cues, we found that two major subpopulations of CeA neurons, Somatostatin-positive (CeASst) and protein kinase Cδ-positive (CeAPKCδ) neurons, can assign motivational properties to environmental cues. Although the proportion of food responsive cells was higher within CeASst than CeAPKCδ neurons, only the activities of CeAPKCδ, but not CeASst, neurons were required for learning of contextual food cues. Our findings point to a model in which CeAPKCδ neurons may incorporate stimulus salience together with sensory features of the environme...

Pupil size has been established as a versatile marker of noradrenergic and cholinergic neuromodulation, which has profound effects on neuronal processing, cognition, and behavior. However, little is known about the cortical control and effects of pupil-linked neuromodulation. Here, we show that pupil dynamics are tightly coupled to temporally, spectrally, and spatially specific modulations of local and large-scale cortical population activity in the human brain. We quantified the dynamics of band-limited cortical population activity in resting human subjects using magnetoencephalography and investigated how neural dynamics were linked to simultaneously recorded pupil dynamics. Our results show that pupil-linked neuromodulation does not merely affect cortical population activity in a stereotypical fashion. Instead, we identified three frontal, precentral, and occipitoparietal networks, in which local population activity with distinct spectral profiles in the theta, beta, and alpha bands temporally preceded ...