Single Exposure to Cocaine Impairs Reinforcement Learning by Potentiating the Activity of Neurons in the Direct Striatal Pathway in Mice

Plasticity in the glutamatergic synapses on striatal medium spiny neurons (MSNs) is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse. Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment. In the present work, we found that the negative reinforcement learning, escaping mild foot-shocks by correct nose-poking, was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice. Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1 (D1) receptor (D1-MSNs). However, 24 h after the cocaine exposure, the potentiation required for reinforcement learning was disrupted. Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice, but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine. The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12264-021-00687-8.     

Noise‐rearing disrupts the maturation of multisensory integration

It is commonly believed that the ability to integrate information from different senses develops according to associative learning principles as neurons acquire experience with co‐active cross‐modal inputs. However, previous studies have not distinguished between requirements for co‐activation versus co‐variation. To determine whether cross‐modal co‐activation is sufficient for this purpose in visual–auditory superior colliculus (SC) neurons, animals were reared in constant omnidirectional noise. By masking most spatiotemporally discrete auditory experiences, the noise created a sensory landscape that decoupled stimulus co‐activation and co‐variance. Although a near‐normal complement of visual–auditory SC neurons developed, the vast majority could not engage in multisensory integration, revealing that visual–auditory co‐activation was insufficient for this purpose. That experience with co‐varying stimuli is required for multisensory maturation is consistent with the role of the SC in detecting and locating biologically significant events, but it also seems likely that this is a general requirement for multisensory maturation throughout the brain.     

Phasic activation of substantia nigra and the ventral tegmental area by chemical stimulation of the superior colliculus: an electrophysiological investigation in the rat

The source of short-latency visual input to midbrain dopaminergic (DA) neurons is not currently known; however, the superior colliculus (SC) is a subcortical visual structure which has response latencies consistently shorter than those recorded for DA neurons in substantia nigra and the ventral tegmental area. To test whether the SC represents a plausible route by which visual information may gain short latency access to the ventral midbrain, the present study examined whether experimental stimulation of the SC can influence the activity of midbrain DA neurons. In urethane-anaesthetized rats, 63 pairs of extracellular recordings were obtained from neurons in the SC and ipsilateral ventral midbrain, before and after local disinhibitory injections of the GABA antagonist bicuculline (20-40 ng/200-400 nL saline) into the SC. Neurons recorded from substantia nigra and the ventral tegmental area were classified as putative DA (25/63, 39.7%) or putative non-DA (38/63, 60.3%). In nearly half the cases (27/63, 42.8%), chemical stimulation of the SC evoked a corresponding increase in neural activity in the ventral midbrain. This excitatory effect did not distinguish between DA and non-DA neurons. In 6/63 cases (9.5%), SC activation elicited a reliable suppression of activity, while the remaining 30/63 cases (47.6%) were unaffected. In almost a third of cases (16/57, 28.1%) intense phasic activation of the SC was associated with correlated phasic activation of neurons in substantia nigra and the ventral tegmental area. These data suggest that the SC is in a position to play an important role in discriminating the appropriate stimulus qualities required to activate DA cells at short latency.     

Development of cortical influences on superior colliculus multisensory neurons: effects of dark‐rearing

Rearing cats from birth to adulthood in darkness prevents neurons in the superior colliculus (SC) from developing the capability to integrate visual and non‐visual (e.g. visual‐auditory) inputs. Presumably, this developmental anomaly is due to a lack of experience with the combination of those cues, which is essential to form associative links between them. The visual‐auditory multisensory integration capacity of SC neurons has also been shown to depend on the functional integrity of converging visual and auditory inputs from the ipsilateral association cortex. Disrupting these cortico‐collicular projections at any stage of life results in a pattern of outcomes similar to those found after dark‐rearing; SC neurons respond to stimuli in both sensory modalities, but cannot integrate the information they provide. Thus, it is possible that dark‐rearing compromises the development of these descending tecto‐petal connections and the essential influences they convey. However, the results of the present experiments, using cortical deactivation to assess the presence of cortico‐collicular influences, demonstrate that dark‐rearing does not prevent the association cortex from developing robust influences over SC multisensory responses. In fact, dark‐rearing may increase their potency over that observed in normally‐reared animals. Nevertheless, their influences are still insufficient to support SC multisensory integration. It appears that cross‐modal experience shapes the cortical influence to selectively enhance responses to cross‐modal stimulus combinations that are likely to be derived from the same event. In the absence of this experience, the cortex develops an indiscriminate excitatory influence over its multisensory SC target neurons.     

Early onset of glutamatergic and GABAergic synaptic activity in the visual layers of the rodent superior colliculus

During postnatal development, the retinocollicular pathway undergoes activity-dependent refinement, resulting in the precise retinotopic map seen in adults. Previous studies established that retinal efferents reach the mouse superior colliculus (SC) by embryonic day 16. Morphologically, synapses were found in the rat SC before birth. As part of an extended project aimed at understanding the development of synaptic transmission in the visual layers of the SC, we report here the presence of functionally active synapses immediately after birth. Circuit activity in mouse SC neurons was detected in horizontal slices of the visual layers using cell-attached voltage clamp. The spontaneous discharge of action potentials was abolished by glutamatergic blockers and facilitated by bicuculline, showing that circuit activity is based on synaptic transmission and that the action of gamma-aminobutyric acid is inhibitory. Using whole-cell voltage clamp, spontaneous glutamatergic postsynaptic currents as well as miniature GABAergic postsynaptic currents were recorded on postnatal day 1. Excitatory and inhibitory postsynaptic currents could also be evoked by electrical stimulation. Glutamatergic postsynaptic currents comprised both (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor-mediated components. The early function of glutamatergic and GABAergic synaptic transmission in the visual layers of SC suggests that SC neurons are able to process information originating from retinal axons immediately after birth.     

Visual adaptation and novelty responses in the superior colliculus

The brain's ability to ignore repeating, often redundant, information while enhancing novel information processing is paramount to survival. When stimuli are repeatedly presented, the response of visually sensitive neurons decreases in magnitude, that is, neurons adapt or habituate, although the mechanism is not yet known. We monitored the activity of visual neurons in the superior colliculus (SC) of rhesus monkeys who actively fixated while repeated visual events were presented. We dissociated adaptation from habituation as mechanisms of the response decrement by using a Bayesian model of adaptation, and by employing a paradigm including rare trials that included an oddball stimulus that was either brighter or dimmer. If the mechanism is adaptation, response recovery should be seen only for the brighter stimulus; if the mechanism is habituation, response recovery ('dishabituation') should be seen for both the brighter and dimmer stimuli. We observed a reduction in the magnitude of the initial transient response and an increase in response onset latency with stimulus repetition for all visually responsive neurons in the SC. Response decrement was successfully captured by the adaptation model, which also predicted the effects of presentation rate and rare luminance changes. However, in a subset of neurons with sustained activity in response to visual stimuli, a novelty signal akin to dishabituation was observed late in the visual response profile for both brighter and dimmer stimuli, and was not captured by the model. This suggests that SC neurons integrate both rapidly discounted information about repeating stimuli and novelty information about oddball events, to support efficient selection in a cluttered dynamic world.     

Unconscious and conscious processing of color rely on activity in early visual cortex: a TMS study

Chromatic information is processed by the visual system both at an unconscious level and at a level that results in conscious perception of color. It remains unclear whether both conscious and unconscious processing of chromatic information depend on activity in the early visual cortex or whether unconscious chromatic processing can also rely on other neural mechanisms. In this study, the contribution of early visual cortex activity to conscious and unconscious chromatic processing was studied using single-pulse TMS in three time windows 40-100 msec after stimulus onset in three conditions: conscious color recognition, forced-choice discrimination of consciously invisible color, and unconscious color priming. We found that conscious perception and both measures of unconscious processing of chromatic information depended on activity in early visual cortex 70-100 msec after stimulus presentation. Unconscious forced-choice discrimination was above chance only when participants reported perceiving some stimulus features (but not color).     

Cognitive processing in the primary visual cortex: from perception to memory

The primary visual cortex is the first cortical area of the visual system that receives information from the external visual world. Based on the receptive field characteristics of the neurons in this area, it has been assumed that the primary visual cortex is a pure sensory area extracting basic elements of the visual scene. This information is then subsequently further processed upstream in the higher-order visual areas and provides us with perception and storage of the visual environment. However, recent findings show that such neural implementations are observed in the primary visual cortex. These neural correlates are expressed by the modulated activity of the late response of a neuron to a stimulus, and most likely depend on recurrent interactions between several areas of the visual system. This favors the concept of a distributed nature of visual processing in perceptual organization.     

The spinning dancer illusion and spontaneous brain fluctuations: An fMRI study

The brain activation associated with the Spinning Dancer Illusion, a cognitive visual illusion, is not entirely known. Inferences from other study modalities point to the involvement of the dorso-parieto-occipital areas in the spontaneous switchings of perception in other bistable non-kinetic illusions. fMRI is a mature technique used to investigate the brain responses associated with mental changes. Resting-state fMRI is a novel technique that may help ascertain the effects of spontaneous brain changes in the top-down regulation of visual perception. The purpose of this report is to describe the brain activation associated with the subjective illusory changes of perception of a kinetic bistable stimulus. We hypothesize that there is a relationship between the perception phases with the very slow cortical spontaneous fluctuations, recently described. A single normal subject who was trained to produce voluntarily perception phase switches underwent a series of fMRI studies whose blocks were either defined post-hoc or accordingly with a predefined timeline to assess spontaneous and voluntarily evoked visual perception switches, respectively. Correlation of findings with resting-state fMRI and independent component analysis of the task series was sought. Phases of the rotation direction were found associated with right parietal activity. Independent component analysis of the task series and their comparison with basal resting-state components suggest that this activity is related to one of the very slow spontaneous brain fluctuations. The spontaneous fluctuations of the cortical activity may explain the subjective changes in perception of direction of the Spinning Dancer Illusion. This observation is a proof-of-principle, suggesting that the spontaneous brain oscillations may influence top-down sensory regulation.     

Adaptation to stimulus orientation in mouse primary visual cortex

Information processing in the visual system is shaped by recent stimulus history, such that prolonged viewing of an adapting stimulus can alter the perception of subsequently presented test stimuli. In the tilt‐after‐effect, the perceived orientation of a grating is often repelled away from the orientation of a previously viewed adapting grating. A possible neural correlate for the tilt‐after‐effect has been described in cat and macaque primary visual cortex (V1), where adaptation produces repulsive shifts in the orientation tuning curves of V1 neurons. We investigated adaptation to stimulus orientation in mouse V1 to determine whether known species differences in orientation processing, notably V1 functional architecture and proportion of tightly tuned cells, are important for these repulsive shifts. Unlike the consistent repulsion reported in other species, we found that repulsion was only about twice as common as attraction in our mouse data. Furthermore, adapted responses were attenuated across all orientations. A simple model that captured key physiological findings reported in cats and mice indicated that the greater proportion of broadly tuned neurons in mice may explain the observed species differences in adaptation.     

Inhibition of superior colliculus neurons by a GABAergic input from the pretectal nuclear complex in the rat

The mammalian pretectal nuclear complex (PNC) is a visual and visuomotor control structure which is strongly connected to other subcortical visual structures. This indicates that the PNC also controls subcortical visual information flow during the execution of various oculomotor programs. A prominent, presumably GABAergic, projection from the PNC targets the superficial grey layer of the superior colliculus (SC), which itself is a central structure for visual information processing necessary for the generation of saccadic eye movements. In order to characterize the pretectotectal projection in vitro, we performed whole-cell patch-clamp recordings from SC and PNC neurons in slices obtained from 3-6-week-old pigmented rats. Focal glutamate injections into the PNC and electrical PNC stimulation were used to induce postsynaptic responses in SC neurons. Electrical stimulation of the SC allowed electrophysiological identification of PNC neurons that provide the inhibitory pretectotectal input. Only inhibitory postsynaptic currents could be elicited in SC neurons both by pharmacological and by electrical activation of the ipsilateral PNC. Concomitantly, a small number of PNC neurons could be antidromically activated from the ipsilateral SC. Most SC cells postsynaptic to the prectectal input showed the dendritic morphology of wide-field and narrow-field cells and are therefore regarded as projection neurons. All inhibitory currents evoked by PNC activation could be completely blocked by bath application of the selective GABA(A) receptor antagonist bicuculline. Together these results indicate that SC projection neurons receive a direct inhibitory input from the ipsilateral PNC and that this input is mediated by GABA(A) receptors.     

Long-range parallel processing and local recurrent activity in the visual cortex of the mouse

The transfer of visual information from the primary visual cortex (V1) to higher order visual cortices is an essential step in visual processing. However, the dynamics of activation of visual cortices is poorly understood. In mice, several extrastriate areas surrounding V1 have been described. Using voltage-sensitive dye imaging in vivo, we determined the spatiotemporal dynamics of the activity evoked in the visual cortex by simple stimuli. Independently of precise areal boundaries, we found that V1 activation is rapidly followed by the depolarization of three functional groups of higher order visual areas organized retinotopically. After this sequential activation, all four regions were simultaneously active for most of the response. Concomitantly with the parallel processing of the visual input, the activity initiated retinotopically and propagated quickly and isotropically within each region. The size of this activation by local recurrent activity, which extended beyond the initial retinotopic response, was dependent on the intensity of the stimulus. Moreover the difference in the spatiotemporal dynamic of the response to dark and bright stimuli suggested the dominance in the mouse of the ON pathway. Our results suggest that the cortex integrates visual information simultaneously through across-area parallel and within-area serial processing.     

Physiological Characterization of Pretectal Neurons Projecting to the Láteral Geniculate Nucleus in the Cat

Single neurons in the pretectal nucleus of the optic tract and posterior pretectal nucleus were extracellularly recorded in anaesthetized cats and tested for antidromic activation after electrical stimulation of the ipsilateral dorsal lateral geniculate nucleus. Cells were further characterized by their response latencies to electrical stimulation of the optic nerve head and the optic chiasm, and by responses to various visual stimuli. 46 out of 188 neurons (24%) were antidromically activated from the lateral geniculate nucleus at response latencies of 0.6 - 2.6 ms. They had low spontaneous activities and preferred fast-moving visual stimuli. 29 of the antidromically activated neurons (63%) could be activated from the optic chiasm with response latencies of 4–10 ms. Together with the mean conduction time of 0.8 ms between the optic nerve head and the optic chiasm, this indicates that they receive an indirect retinal input via fast-conducting Y-fibres. Sometimes antidromically activated neurons spontaneously showed irregular burst activity. During unidirectional stimulation with a large moving visual stimulus, burst activity became more regular, and interburst intervals and the duration of single bursts decreased. After the stimulus was stopped, interburst intervals slowly increased until prestimulation activity was restored. The response properties of these neurons could reflect the transfer of saccade-related visual as well as oculomotor signals through the pretectum to the visual thalamus.     

Stimulus discrimination via responses of retinal ganglion cells and dopamine-dependent modulation

Neighboring retinal ganglion cells（RGCs）fire with a high degree of correlation.It has been increasingly realized that visual perception of the environment relies on neuronal population activity to encode and transmit the information contained in stimuli.Understanding how neuronal population activity contributes to visual information processing is essential for understanding the mechanisms of visual coding.Here we simultaneously recorded spike discharges from groups of RGCs in bullfrog retina in response to visual patterns（checkerboard,horizontal grating,and full-field illumination）using a multi-electrode array system.To determine the role of synchronous activity mediated by gap junctions,we measured the correct classification rates of single cells＇firing patterns as well as the synchronization patterns of multiple neurons.We found that,under normal conditions,RGC population activity exhibited distinct response features with exposure to different stimulus patterns and had a higher rate of correct stimulus discrimination than the activity of single cells.Dopamine（1μmol/L）application did not significantly change the performance of single neuron activity,but enhanced the synchronization of the RGC population activity and decreased the rate of correct stimulus pattern discrimination.These findings suggest that the synchronous activity of RGCs plays an important role in the information coding of different types of visual patterns,and a dopamine-induced increase in synchronous activity weakens the population performance in pattern discrimination,indicating the potential role of the dopaminergic pathway in modulating the population coding process.     

Nicotinic activity layer specifically modulates synaptic potentiation in the mouse insular cortex

Nicotinic acetylcholine receptors (nAChRs) in the insular cortex play an important role in nicotine addiction, but its cellular and synaptic mechanisms underlying nicotine addiction still remain unresolved. In layer 5 pyramidal neurons of the mouse insular cortex, activation of nAChRs suppresses synaptic potentiation through enhancing GABAergic synaptic transmission via activation of β2‐containing nAChRs in non‐fast‐spiking (non‐FS) interneurons. However, it has not been addressed whether and how activation of nAChRs modulates synaptic plasticity in layers 3 and 6 pyramidal neurons of the insular cortex. In this study, I demonstrate that activation of nAChRs oppositely modulates synaptic potentiation in layers 3 and 6 pyramidal neurons of the insular cortex. In layer 3 pyramidal neurons, activation of nAChRs depressed synaptic potentiation induced by combination of presynaptic stimulation with postsynaptic depolarization (paired training) through enhancing GABAergic synaptic transmission via activation of β2‐containing nAChRs in non‐FS interneurons. By contrast, in layer 6 pyramidal neurons, activation of nAChRs enhanced synaptic potentiation through activating postsynaptic β2‐containing nAChRs. These results indicate, in different layers of the mouse insular cortex, paired training‐induced synaptic potentiation is oppositely regulated by activation of nAChRs which are located on GABAergic interneurons (layer 3) and on pyramidal neurons (layer 6). Thus, layer‐specific modulation of synaptic potentiation may be involved in cellular and synaptic mechanisms of insular cortical changes in nicotine addiction.     

Fleeting images: rapid affect discrimination in the visual cortex

Converging electrophysiological and hemodynamic findings indicate sensory processing of emotional pictures is preferred to that of neutral pictures. Whereas neuroimaging studies of emotional picture perception have employed stimulus durations lasting several seconds, recent electrocortical investigations report early visual cortical discrimination between emotionally arousing and neutral picture processing. Here, we use a hybrid picture presentation paradigm covering a range of rapid presentation rates (0.75-6 Hz), while visual system activity is recorded with functional magnetic resonance imaging. Results demonstrate widespread sensitivity to emotional arousal in the secondary and inferior temporal visual cortex. Furthermore, activity in the lateral inferior occipital and medial inferior temporal visual cortex revealed equivalent emotion-sensitive activation across all presentation rates. Results further support the notion that attention and perceptual processing are in part directed by underlying motivational systems.     

Dynamics of a Mutual Inhibition Circuit between Pyramidal Neurons Compared to Human Perceptual Competition

Neural competition plays an essential role in active selection processes of noisy and ambiguous input signals, and it is assumed to underlie emergent properties of brain functioning, such as perceptual organization and decision-making. Despite ample theoretical research on neural competition, experimental tools to allow neurophysiological investigation of competing neurons have not been available. We developed a “hybrid” system where real-life neurons and a computer-simulated neural circuit interacted. It enabled us to construct a mutual inhibition circuit between two real-life pyramidal neurons. We then asked what dynamics this minimal unit of neural competition exhibits and compared them with the known behavioral-level dynamics of neural competition. We found that the pair of neurons shows bistability when activated simultaneously by current injections. The addition of modeled synaptic noise and changes in the activation strength showed that the dynamics of the circuit are strikingly similar to the known properties of bistable visual perception: The distribution of dominance durations showed a right-skewed shape, and the changes of the activation strengths caused changes in dominance, dominance durations, and reversal rates as stated in the well-known empirical laws of bistable perception known as Levelt''s propositions.SIGNIFICANCE STATEMENT Visual perception emerges as the result of neural systems actively organizing visual signals that involves selection processes of competing neurons. While the neural competition, realized by a “mutual inhibition” circuit has been examined in many theoretical studies, its properties have not been investigated in real neurons. We have developed a “hybrid” system where two real-life pyramidal neurons in a mouse brain slice interact through a computer-simulated mutual inhibition circuit. We found that simultaneous activation of the neurons leads to bistable activity. We investigated the effect of noise and the effect of changes in the activation strength on the dynamics. We observed that the pair of neurons exhibit dynamics strikingly similar to the known properties of bistable visual perception.     

Responses of neurons in the Clare-Bishop cortical association area of the cat cerebral cortex to photic stimulation

In acute experiments on cats with protrigeminal section immobilized by flaxedil the electrical activity of single neurons in associative visual cortex of Clare-Bishop was investigated by the extracellular registration of their spike activity. 95.5% of investigated neurons responding to natural stimulation (light spots) were sensitive to the movement of stimulus through the receptive field. Nearly 55% of neurons exhibited selective responses to the direction of stimulus movement. Some neurones responded only when the stimulus was crossing the border points of receptive field. Nearly 85.3% of neurons responded to the flashing spot with "on", "on-off" and "off" reactions, and also to the stimulation by diffuse flashes. Receptive fields of neurons in the Clare-Bishop area were of strip-like form with longitudinal axis in horizontal orientation. Presented observations allow concluding that the Clare-Bishop cortical association area plays an essential role in the central processing of visual information.     

Neural correlates of time distortion in a preaction period

An intention to move distorts the perception of time. For example, a visual stimulus presented during the preparation of manual movements is perceived longer than actual. Although neural mechanisms underlying this action‐induced time distortion have been unclear, here we propose a new model in which the distortion is caused by a sensory–motor interaction mediated by alpha rhythm. It is generally known that viewing a stimulus induces a reduction in amplitude of occipital 10‐Hz wave (“alpha‐blocking”). Preparing manual movements are also known to reduce alpha power in the motor cortex (“mu‐suppression”). When human participants prepared movements while viewing a stimulus, we found that those two types of classical alpha suppression interacted in the third (time‐processing) region in the brain, inducing a prominent decrease in alpha power in the supplementary motor cortex (SMA). Interestingly, this alpha suppression in the SMA occurred in an asymmetric manner (such that troughs of alpha rhythm was more strongly suppressed than peaks), which can produce a gradual increase (slow shift of baseline) in neural activity. Since the neural processing in the SMA encodes a subjective time length for a sensory event, the increased activity in this region (by the asymmetric alpha suppression) would cause an overestimation of elapsed time, resulting in the action‐induced time distortion. Those results showed a unique role of alpha wave enabling communications across distant (visual, motor, and time‐processing) regions in the brain and further suggested a new type of sensory–motor interaction based on neural desynchronization (rather than synchronization).     

Postnatal development of corticotectal neurons in the kitten striate cortex: an electrophysiological study

In cats ranging in age from the second week to adult, the postnatal functional development of striate cortical neurons projecting to the superior colliculus (SC) was studied by observing their visual responses, axonal conduction velocities and spontaneous activities. One-hundred-and-fifty-seven cells were identified as projecting to the SC (C-T cells) on the basis of antidromic activation from SC. At the second week of age, 57% of the C-T cells had receptive fields of the complex type and the others were visually unresponsive. C-T cells with 'special complex' properties, which are characteristic of the adult C-T cells, first appeared at the third week and made up 19% of the total. The proportion of such C-T cells increased very rapidly and attained the adult-like value at the fourth week. The spontaneous activity of the C-T cells was very sparse or absent at the second week and increased thereafter with age. The proportion of cells with the high level of spontaneous activity found in the adult increased with the same time-course as did the special complex cells. The axonal conduction velocity of C-T cells was slower than 2 m/s until the third week. C-T cells with the faster velocities, suggestive of axonal myelination, appeared at the fourth week and thereafter the average value increased very rapidly until the weeks 8-9. These results indicate that the most remarkable functional development of C-T cells may occur around the fourth week of age. By comparison with previous data on postnatal development of neurons in the cortex and SC, we suggest that C-T cells may be one of the early-maturing groups of cells in the striate cortex and their maturation may exert a crucial influence on the development of visual response properties of SC neurons.