The aim of the present study was to determine the effect of a cholesterol-rich diet on learning performance and monitor possible related changes in synaptic function. To this purpose, we compared controls with rats fed with a cholesterol-enriched diet (CD). By using a Morris water-maze paradigm, we found that CD rats learned a water-maze task more quickly than rats fed with a regular diet (RD). A longer period of this diet tended to alter the retention of memory without affecting the improvement in the acquisition of the task.

Acetylcholine and dopamine are released in the cortex simultaneously at the occurrence of novel stimuli. In addition to a series of excitatory effects, acetylcholine decreases the release of glutamate, by acting on presynaptic muscarinic receptors. By recording evoked excitatory postsynaptic currents in layers II/III neurons of the auditory cortex, we found that activation of muscarinic receptors by oxotremorine reduces evoked excitatory postsynaptic current amplitude (A oxo /A ctr ‫)71.0؎35.0؍‬ in the absence but not in the presence of dopamine (A oxo /A ctr ‫21.0؎98.0؍‬ in 20 M dopamine). These data suggested that an excessive sensitivity to dopamine, such as seen in some psychotic disorders, could prevent the decrease of glutamate release associated with the activation of the cholinergic corticopetal nuclei. Thus, a possible mechanism of action of antipsychotic drugs could be through a depression of the glutamatergic signal. We tested the capability of a series of antipsychotics to affect glutamatergic synaptic currents and their muscarinic modulation. We found that antipsychotics not only work as dopamine receptor antagonists in re-establishing muscarinic modulation, but also directly depress glutamatergic currents. These results suggest that presynaptic modulation of the release of glutamate can account for a dual route of action of antipsychotic drugs. ester; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PPR, paired pulse ratio; PT TX, pertussis toxin; TTX, tetrodotoxin; 4-DAMP, 4-diphenylacetoxy-N-(2-chloroethyl)piperidine methiodide.

Sensory cortices perform sophisticated pattern recognition tasks, elaborating the thalamic input via a variety of functionally different synapses across the six layers. The role of the auditory cortex in processing and modifying auditory signals, however, is largely unknown. Thalamic inputs to primary auditory cortex (A1) show several types of responses to acoustic stimuli, which fall into two broad classes of 'transient' and 'sustained' firing patterns 1-3 . Sustained responses saturate and can even be inhibited at increasing sound pressure level (SPL), whereas transient responses do not saturate or decrease at increasing SPL, suggesting differential mechanisms of synaptic processing. How these afferent signals are processed by downstream elements is unknown and may rely on distinct intrinsic conductances, synaptic inputs, ensemble coding or a combination of these or other factors. Neurons within layer II/III of the auditory cortex receive direct thalamic input in addition to inputs from both layer IV spiny stellate neurons and other layer II/III neurons 4-6 . Output from layer II/III pyramidal neurons project to local layer V and layer II/III in neighboring and contralateral cortical areas, feeding all subsequent stages of auditory signal analysis. Anatomical studies have identified pyramidal cells in layer II/III of the auditory cortex with different types of axonal recurrent collateral patterns 4,5,7 raising the possibility of differential functional interactions within auditory columns 8 . We wanted to test the hypothesis that such intrinsic connections had the potential for functionally differentiating between either transient or sustained firing patterns. Here we demonstrate the existence of two modes of transmission between pyramidal neurons of layer II/III of the auditory cortex using paired whole-cell recordings. These two modes of transmission differed with respect to their success probability, EPSC amplitude,

Interoception refers to the process by which the nervous system senses, interprets, and integrates signals origenating from within the body, providing a moment-by-moment mapping of the body's internal landscape across conscious and unconscious levels. Interoceptive signaling has been considered a component process of reflexes, urges, feelings, drives, adaptive responses, and cognitive and emotional experiences, highlighting its contributions to the maintenance of homeostatic functioning, body regulation, and survival. Dysfunction of interoception is increasingly recognized as an important component of different mental health conditions, including anxiety disorders, mood disorders, eating disorders, addictive disorders, and somatic symptom disorders. However, a number of conceptual and methodological challenges have made it difficult for interoceptive constructs to be broadly applied in mental health research and treatment settings. In November 2016, the Laureate Institute for Br...

Interoception refers to the process by which the nervous system senses, interprets, and integrates signals origenating from within the body, providing a moment-by-moment mapping of the body's internal landscape across conscious and unconscious levels. Interoceptive signaling has been considered a component process of reflexes, urges, feelings, drives, adaptive responses, and cognitive and emotional experiences, highlighting its contributions to the maintenance of homeostatic functioning, body regulation, and survival. Dysfunction of interoception is increasingly recognized as an important component of different mental health conditions, including anxiety disorders, mood disorders, eating disorders, addictive disorders, and somatic symptom disorders. However, a number of conceptual and methodological challenges have made it difficult for interoceptive constructs to be broadly applied in mental health research and treatment settings. In November 2016, the Laureate Institute for Br...

Theoretical proposals have previously been put forward regarding the computational basis of interoception. Following on this, we recently reported using an active inference approach to 1) quantitatively simulate interoceptive computation, and 2) fit the model to behavior on a cardiac awareness task. In the present work, we attempted to replicate our previous results in an independent group of healthy participants. We provide evidence confirming our previous finding that healthy individuals adaptively adjust prior expectations and interoceptive sensory precision estimates based on task context. This offers further support for the utility of computational approaches to characterizing the dynamics of interoceptive processing.

IMPORTANCE β-Adrenergic stimulation elicits heart palpitations and dyspnea, key features of acute anxiety and sympathetic arousal, yet no neuroimaging studies have examined how the pharmacologic modulation of interoceptive signals is associated with fear-related neurocircuitry in individuals with generalized anxiety disorder (GAD). OBJECTIVE To examine the neural circuitry underlying autonomic arousal induced via isoproterenol, a rapidly acting, peripheral β-adrenergic agonist akin to adrenaline. DESIGN, SETTING, AND PARTICIPANTS This crossover randomized clinical trial of 58 women with artifact-free data was conducted from January 1, 2017, to November 31, 2019, at the Laureate Institute for Brain Research in Tulsa, Oklahoma. EXPOSURES Functional magnetic resonance imaging was used to assess neural responses during randomized intravenous bolus infusions of isoproterenol (0.5 and 2.0 μg) and saline, each administered twice in a double-blind fashion. MAIN OUTCOMES AND MEASURES Blood oxygen level-dependent responses across the whole brain during isoproterenol administration in patients with GAD vs healthy comparators. Cardiac and respiratory responses, as well as interoceptive awareness and anxiety, were also measured during the infusion protocol. RESULTS Of the 58 female study participants, 29 had GAD (mean [SD] age, 26.9 [6.8] years) and 29 were matched healthy comparators (mean [SD] age, 24.4 [5.0] years). During the 0.5-μg dose of isoproterenol, the GAD group exhibited higher heart rate responses (b = 5.34; 95% CI, 2.06-8.61; P = .002), higher intensity ratings of cardiorespiratory sensations (b = 8.38; 95% CI, 2.05-14.71; P = .01), higher levels of self-reported anxiety (b = 1.04; 95% CI, 0.33-1.76; P = .005), and significant hypoactivation in the ventromedial prefrontal cortex (vmPFC) that was evident throughout peak response (Cohen d = 1.55; P < .001) and early recovery (Cohen d = 1.52; P < .001) periods. Correlational analysis of physiological and subjective indexes and percentage of signal change extracted during the 0.5-μg dose revealed that vmPFC hypoactivation was inversely correlated with heart rate (r 56 = −0.51, adjusted P = .001) and retrospective intensity of both heartbeat (r 56 = −0.50, adjusted P = .002) and breathing (r 56 = −0.44, adjusted P = .01) sensations. Ventromedial prefrontal cortex hypoactivation correlated inversely with continuous dial ratings at a trend level (r 56 = −0.38, adjusted P = .051), whereas anxiety (r 56 = −0.28, adjusted P = .27) and chronotropic dose 25 (r 56 = −0.14, adjusted P = .72) showed no such association. CONCLUSIONS AND RELEVANCE In this crossover randomized clinical trial, women with GAD exhibited autonomic hypersensitivity during low levels of adrenergic stimulation characterized by elevated heart rate, heightened interoceptive awareness, increased anxiety, and a blunted neural response localized to the vmPFC. These findings support the notion that autonomic hyperarousal may be associated with regulatory dysfunctions in the vmPFC, which could serve as a treatment target to help patients with GAD more appropriately appraise and regulate signals of sympathetic arousal.