Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation ( P FDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC...

The dynamics of information flow within the auditory cortical hierarchy associated with speech processing and the emergence of hemispheric specialization remain incompletely understood. To study these questions with high spatiotemporal resolution, intracranial recordings in 29 human neurosurgical patients of both sexes were obtained while subjects performed a semantic classification task. Neural activity was recorded from posteromedial portion of Heschl's gyrus (HGPM) and anterolateral portion of Heschl's gyrus (HGAL), planum temporale (PT), planum polare, insula, and superior temporal gyrus (STG). Responses to monosyllabic words exhibited early gamma power increases and a later suppression of alpha power, envisioned to represent feedforward activity and decreased feedback signaling, respectively. Gamma activation and alpha suppression had distinct magnitude and latency profiles. HGPM and PT had the strongest gamma responses with shortest onset latencies, indicating that they are the earliest auditory cort...

Speech is an intrinsically multisensory signal and seeing the speaker's lips forms a cornerstone of communication in acoustically impoverished environments. Still, it remains unclear how the brain exploits visual speech for comprehension. Previous work debated whether lip signals are mainly processed along the auditory pathways or whether the visual system directly implements speech-related processes. To probe this, we systematically characterized dynamic representations of multiple acoustic and visual speech-derived features in source localized MEG recordings that were obtained while participants listened to speech or viewed silent speech. Using a mutual-information framework we provide a comprehensive assessment of how well temporal and occipital cortices reflect the physically presented signals and unique aspects of acoustic features that were physically absent but may be critical for comprehension. Our results demonstrate that both cortices feature a functionally specific form of multisensory restorati...

Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BL/6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential µ-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central ...

How do animals experience brain manipulations? Optogenetics has allowed us to manipulate selectively and interrogate neural circuits underlying brain function in health and disease. However, little is known about whether mice can detect and learn from arbitrary optogenetic perturbations from a wide range of brain regions to guide behavior. To address this issue, mice were trained to report optogenetic brain perturbations to obtain rewards and avoid punishments. Here we found that mice can perceive optogenetic manipulations regardless of the perturbed brain area, rewarding effects, or the stimulation of glutamatergic, GABAergic, and dopaminergic cell types. We named this phenomenon optoception, a perceptible signal internally generated from perturbing the brain, as occurs with interoception. Using optoception, mice can learn to execute two different sets of instructions based on the laser frequency. Importantly, optoception can occur either activating or silencing a single cell type. Moreover, stimulation o...

The ability to encode and retrieve contextual information is an inherent feature of episodic memory that starts to develop during childhood. The postrhinal cortex, an area of the parahippocampal region, has a crucial role in encoding object-space information and translating egocentric to allocentric representation of local space. The strong connectivity of POR with the adjacent entorhinal cortex, and consequently the hippocampus, suggests that the development of these connections could support the postnatal development of contextual memory. Here, we report that postrhinal cortex projections of the rat develop progressively from the first to the third postnatal week starting in the medial entorhinal cortex before spreading to the lateral entorhinal cortex. The increased spread and complexity of postrhinal axonal distributions is accompanied by an increased complexity of entorhinal dendritic trees and an increase of postrhinal – entorhinal synapses, which supports a gradual maturation in functional activity....

Schemata enhance memory formation for related novel information. This is true even when this information is neutral with respect to schema-driven expectations. This assimilation of novel information into schemata has been attributed to more effective organizational processing that leads to more referential connections with the activated associative schema network. Animal data suggest that systems consolidation of novel assimilated information is also accelerated. In the current study, we used both multivariate and univariate fMRI analyses to provide further support for these proposals and to elucidate the neural underpinning of these processes. 28 Participants (5 male) over-learned fictitious schemata for seven weeks and then encoded novel related and control facts in the scanner. These facts were retrieved both immediately and two weeks later, also in the scanner. Our results conceptually replicate previous findings with respect to enhanced vmPFC-hippocampus coupling during encoding of novel related infor...

Metabolic state can alter olfactory sensitivity, but it is unknown if the activity of the olfactory bulb (OB) may fine tune metabolic homeostasis. Our objective was to use CRISPR gene editing in male and female mice to enhance the excitability of mitral/tufted projection neurons (M/TCs) of the OB to test for improved metabolic health. Ex vivo slice recordings of MCs in CRIPSR mice confirmed increased excitability due the targeted loss of Kv1.3 channels, which resulted in a less negative resting membrane potential, enhanced action potential firing, and insensitivity to the selective channel blocker margatoxin. CRISPR mice exhibited enhanced odor discrimination using a habituation/dishabituation paradigm. CRISPR mice were challenged for 25 weeks with a moderately high-fat diet, and compared with littermate controls, male mice were resistance to diet-induced obesity (DIO). Female mice did not exhibit DIO. CRISPR male mice gained less body weight, accumulated less white adipose tissue, cleared a glucose challe...

N-Methyl-D-aspartic (NMDA) receptors are ionotropic glutamate receptors widely expressed in the central nervous system, where they mediate phenomena as diverse as neurotransmission, information processing, synaptogenesis, and cellular toxicity. They function as glutamate-gated Ca2+-permeable channels, which require glycine as co-agonist, and can be modulated by many diffusible ligands and cellular cues, including mechanical stimuli. Previously, we found that in cultured astrocytes, shear stress initiates NMDA receptor-mediated Ca2+ entry in the absence of added agonists, suggesting that more than being mechanosensitive, NMDA receptors may be mechanically activated. Here, we used controlled expression of rat recombinant receptors and non-invasive on-cell single-channel current recordings to show that mild membrane stretch can substitute for the neurotransmitter glutamate in gating NMDA receptor currents. Notably, stretch-activated currents maintained the hallmark features of the glutamate-gated currents, in...

Extinguishing the previously acquired fear is critical for organism’s adaptation to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically-situated, δ subunit-containing GABAARs (GABAA(δ)Rs), had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic subregion (IL), sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also show...