An interoceptive predictive coding model of conscious presence

We describe a theoretical model of the neurocognitive mechanisms underlying conscious presence and its disturbances. The model is based on interoceptive prediction error and is informed by predictive models of agency, general models of hierarchical predictive coding and dopaminergic signaling in cortex, the role of the anterior insular cortex (AIC) in interoception and emotion, and cognitive neuroscience evidence from studies of virtual reality and of psychiatric disorders of presence, specifically depersonalization/derealization disorder. The model associates presence with successful suppression by top-down predictions of informative interoceptive signals evoked by autonomic control signals and, indirectly, by visceral responses to afferent sensory signals. The model connects presence to agency by allowing that predicted interoceptive signals will depend on whether afferent sensory signals are determined, by a parallel predictive-coding mechanism, to be self-generated or externally caused. Anatomically, we identify the AIC as the likely locus of key neural comparator mechanisms. Our model integrates a broad range of previously disparate evidence, makes predictions for conjoint manipulations of agency and presence, offers a new view of emotion as interoceptive inference, and represents a step toward a mechanistic account of a fundamental phenomenological property of consciousness

Functional role of basal ganglia in normal and pathological behaviour

The basal ganglia (BG) appear to exert their major influence on motor functions and their related different behavioral activities. It has been proposed that the BG subserve relatively automatic responses to sensory inputs involving high-level functions like behavioural learning and procedural memory. Moreover, BG play a key role in the processes driving motor performance including emotion, motivation and reward. Severe neurological and neuropsychiatric disorders such as Parkinson’s disease (PD), ballism, Huntington’s chorea, Tourette’s syndrome and obsessive-compulsive disorder have been linked to BG dysfunctions. This article emphasizes the role of the BG in appropriate behavioural response to environmental cues suggesting that the inability to execute specific behavioural sequences may be explained by localized deficits as well as by alterations affecting complex cortico-basal ganglia circuits.peer-reviewe

Excitatory postsynaptic potentials in rat neocortical neurons in vitro. III. Effects of a quinoxalinedione non-NMDA receptor antagonist

1. Intracellular microelectrodes were used to obtain recordings from neurons in layer II/III of rat frontal cortex. A bipolar electrode positioned in layer IV of the neocortex was used to evoke postsynaptic potentials. Graded series of stimulation were employed to selectively activate different classes of postsynaptic responses. The sensitivity of postsynaptic potentials and iontophoretically applied neurotransmitters to the non-N-methyl-D-asparate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) was examined. 2. As reported previously, low-intensity electrical stimulation of cortical layer IV evoked short-latency early excitatory postsynaptic potentials (eEPSPs) in layer II/III neurons. CNQX reversibly antagonized eEPSPs in a dose-dependent manner. Stimulation at intensities just subthreshold for activation of inhibitory postsynaptic potentials (IPSPs) produced long-latency (10 to 40-ms) EPSPs (late EPSPs or 1EPSPs). CNQX was effective in blocking 1EPSPs. 3. With the use of stimulus intensities at or just below threshold for evoking an action potential, complex synaptic potentials consisting of EPSP-IPSP sequences were observed. Both early, Cl(-)-dependent and late, K(+)-dependent IPSPs were reduced by CNQX. This effect was reversible on washing. This disinhibition could lead to enhanced excitability in the presence of CNQX. 4. Iontophoretic application of quisqualate produced a membrane depolarization with superimposed action potentials, whereas NMDA depolarized the membrane potential and evoked bursts of action potentials. At concentrations up to 5 microM, CNQX selectively antagonized quisqualate responses. NMDA responses were reduced by 10 microM CNQX. D-Serine (0.5-2 mM), an agonist at the glycine regulatory site on the NMDA receptor, reversed the CNQX depression of NMDA responses

Neural and Behavioral Mechanisms of Interval Timing in the Striatum

To guide behavior and learn from its consequences, the brain must represent time over many scales. Yet, the neural signals used to encode time in the seconds to minute range are not known. The striatum is the major input area of the basal ganglia; it plays important roles in learning, motor function and normal timing behavior in the range of seconds to minutes. We investigated how striatal population activity might encode time. To do so, we recorded the electrical activity from striatal neurons in rats performing the serial fixed interval task, a dynamic version of the fixed Interval schedule of reinforcement. The animals performed in conformity with proportional timing, but did not strictly conform to scalar timing predictions, which might reflect a parallel strategy to optimize the adaptation to changes in temporal contingencies and consequently to improve reward rate over the session. Regarding the neural activity, we found that neurons fired at delays spanning tens of seconds and that this pattern of responding reflected the interaction between time and the animals’ ongoing sensorimotor state. Surprisingly, cells rescaled responses in time when intervals changed, indicating that striatal populations encoded relative time. Moreover, time estimates decoded from activity predicted trial-bytrial timing behavior as animals adjusted to new intervals, and disrupting striatal function with local infusion of muscimol led to a decrease in timing performance. Because of practical limitations in testing for sufficiency a biological system, we ran a simple simulation of the task; we have shown that neural responses similar to those we observe are conceptually sufficient to produce temporally adaptive behavior. Furthermore, we attempted to explain temporal processes on the basis of ongoing behavior by decoding temporal estimates from high-speed videos of the animals performing the task; we could not explain the temporal report solely on basis of ongoing behavior. These results suggest that striatal activity forms a scalable population firing rate code for time, providing timing signals that animals use to guide their actions

Circuit-level analyses of cortico-basal ganglia-thalamic networks. Effects of dopamine dysregulation and experience dependent plasticity.

The cortico-basal ganglia-thalamic (CBT) circuit is thought to be involved in control of voluntary and goal-directed movements and action selection. Dopamine is known to play a crucial role in this circuit and regulating its activity. The important role of dopamine is particularly evident in Parkinson’s patients, where dopaminergic cells are dying and motor impairments follow. While dopamine replacement is an effective therapy, satisfactory alleviation only lasts for a limited number of years, after which patients frequently develop side-effects in the form of levodopa-induced dyskinesia. In order to clarify the neurophysiological consequences of dopamine dysregulation we have here investigated the electrophysiological activity of each part of the CBT-loop in rats during different experimental conditions, using custom made multi-channel electrodes. Neuronal activity changes in 16 CBT structures were characterized upon acute pharmacological dopaminergic manipulations and firing rate changes of subgroup of cells within different structures in the CBT circuit were shown to potentially be responsible for the severe akinesia induced by the drugs. We have also developed a novel method to monitor the global state of the CBT circuit in a rat model of levodopa-induced dyskinesia and showed how this approach can be used to help developing new pharmacological therapies. Lastly, to investigate how somatosensory input is affecting motor circuits, we have recorded activity of the whole CBT-loop in rats before and after extensive skilled forelimb reaching and grasping training. Preliminary results show that only the motor cortex display experience-dependent changes due to the reaching training

Pharmacological manipulation of NMDA receptor activation and synaptic norepinephrine levels: Effects on sustained attention in male rats

Impaired attention is common in many neurological disorders. Normal attention promotes the selective processing of important sensory information. This selective processing relies on neurotransmitters, like glutamate, and neuromodulators, like norepinephrine, acting in frontal, parietal, and visual cortices. We tested treatments targeting the glutamatergic and noradrenergic systems using a rat model of attentional lapses.Rats were trained to respond quickly to stimuli in a two-choice reaction time task (2CRTT). Response times were split into initiation time (IT) and movement time (MT). Performance measures were derived from IT and MT distributions. IT mode represents sensorimotor processing speed when rats are attentive. IT deviation from mode (devmode) measures distribution skew which is thought to reflect attentional lapses. Altered MT mode or trials completed could reflect drug-induced side-effects. We tested the NMDA receptor co-agonist, D-serine, in a group of rats. We then tested a combination treatment of D-serine and the norepinephrine reuptake inhibitor, atomoxetine (ATX). New rats were used in a follow-up test. Data were analyzed using linear mixed models or repeated measures ANOVA. We did not find an effect of D-serine on IT mode; however, the highest dose (300 mg/kg) reduced IT devmode. The initial test of the combination treatment (100 mg/kg D-serine with 0.5 mg/kg ATX) did not reveal an effect on IT mode; however, the combination treatment reduced IT devmode with no effect following either drug alone. The follow-up test (125 mg/kg D-serine with 0.3 mg/kg ATX) did not reveal an effect on IT mode; however, IT devmode was reduced following ATX or the combination treatment. Importantly, the combination treatment reduced IT devmode more than either drug alone. Furthermore, the combination treatment did not increase MT mode or trials completed compared to ATX alone. Activating NMDA receptors with D-serine appears to reduce attentional lapses without affecting sensorimotor processing speed. The present findings also support the efficacy of a combination treatment comprising D-serine and ATX. This combination treatment does not appear to increase unwanted side-effects associated with ATX. Taken together, these findings suggest that simultaneously targeting glutamate and NE systems could be a safe and effective strategy for treating impaired attention

Vision: how to train visual cortex to predict reward time.

Little is known about how the brain learns to anticipate the timing of reward. A new study demonstrates that optogenetic activation of basal forebrain input is sufficient to train reward timing activity in the primary visual cortex