The Impact of Prefrontal Cortex for Selective Attention in a Visual Working Memory Task

In this study, a variant of the n-back task was used to investigate electrophysiological correlates of top-down processes in visual-object working memory. Event-related potentials were used to replicate results concerning an attention related modulation of neural processes and to investigate the involvement of prefrontal cortex in this modulation. 16 healthy subjects executed an n-back task with sequentially presented faces and scenes. Attention was selectively directed to only one stimulus category. We found an enhancement of the N170 amplitudes for relevant stimuli compared to irrelevant or neutral stimuli. Late frontal amplitudes were stronger positive for relevant compared to neutral stimuli indicating selective attention processes of working memory. Evidence for selective inhibition was not found.     

Emergence of Nonlinear Mixed Selectivity in Prefrontal Cortex after Training

Neurons in the PFC are typically activated by different cognitive tasks, and also by different stimuli and abstract variables within these tasks. A single neuron''s selectivity for a given stimulus dimension often changes depending on its context, a phenomenon known as nonlinear mixed selectivity (NMS). It has previously been hypothesized that NMS emerges as a result of training to perform tasks in different contexts. We tested this hypothesis directly by examining the neuronal responses of different PFC areas before and after male monkeys were trained to perform different working memory tasks involving visual stimulus locations and/or shapes. We found that training induces a modest increase in the proportion of PFC neurons with NMS exclusively for spatial working memory, but not for shape working memory tasks, with area 9/46 undergoing the most significant increase in NMS cell proportion. We also found that increased working memory task complexity, in the form of simultaneously storing location and shape combinations, does not increase the degree of NMS for stimulus shape with other task variables. Lastly, in contrast to the previous studies, we did not find evidence that NMS is predictive of task performance. Our results thus provide critical insights on the representation of stimuli and task information in neuronal populations, in working memory.SIGNIFICANCE STATEMENT How multiple types of information are represented in working memory remains a complex computational problem. It has been hypothesized that nonlinear mixed selectivity allows neurons to efficiently encode multiple stimuli in different contexts, after subjects have been trained in complex tasks. Our analysis of prefrontal recordings obtained before and after training monkeys to perform working memory tasks only partially agreed with this prediction, in that nonlinear mixed selectivity emerged for spatial but not shape information, and mostly in mid-dorsal PFC. Nonlinear mixed selectivity also displayed little modulation across either task complexity or correct performance. These results point to other mechanisms, in addition to nonlinear mixed selectivity, representing complex information about stimulus and task context in neuronal activity.     

Visual topography of area TEO in the macaque.

Previous studies have mapped the visuotopic organization of visual areas from V1 through V4 in the occipital cortex and of area TE in the temporal cortex, but the cortex in between, at the occipito-temporal junction, has remained relatively unexplored. To determine the visuotopic organization of this region, receptive fields were mapped at 1,200 visually responsive sites on 370 penetrations in the ventral occipital and temporal cortex of five macaques. We identified a new visual area, roughly corresponding to cytoarchitectonic area TEO, located between the ventral portion of V4 and area TE. Receptive fields in TEO are intermediate in size between those in V4 and TE and have a coarse visuotopic organization. Collectively, receptive fields in TEO appear to cover nearly the entire contralateral visual field. The foveal and parafoveal representation of TEO is located laterally on the convexity of the inferior temporal gyrus, and the peripheral field is represented medially on the ventral surface of the hemisphere, within and medial to the occipitotemporal sulcus. Beyond the medial border of TEO, within cyteoarchitectonic area TF, is another visually responsive region, which we have termed VTF; this region may also have some crude visual topography. Bands of constant eccentricity in TEO appear to be continuous with those in V2, V3v, and V4. The upper field representation in TEO is located adjacent to that in ventral V4, with a representation of the horizontal meridian forming the boundary between the two areas. The lower field representation in TEO is located just anterior to the upper field but is smaller. In contrast to the orderly representation of eccentricity in TEO, we found little consistent representation of polar angle, other than the separation of upper and lower fields. The results of injecting anatomical tracers in two animals suggest that TEO is an important link in the pathway that relays visual information from V1 to the inferior temporal cortex. TEO is thus likely to play an important role in pattern perception.     

Activity Subspaces in Medial Prefrontal Cortex Distinguish States of the World

Medial prefrontal cortex (mPfC) activity represents information about the state of the world, including present behavior, such as decisions, and the immediate past, such as short-term memory. Unknown is whether information about different states of the world are represented in the same mPfC neural population and, if so, how they are kept distinct. To address this, we analyze here mPfC population activity of male rats learning rules in a Y-maze, with self-initiated choice trials to an arm end followed by a self-paced return during the intertrial interval (ITI). We find that trial and ITI population activity from the same population fall into different low-dimensional subspaces. These subspaces encode different states of the world: multiple features of the task can be decoded from both trial and ITI activity, but the decoding axes for the same feature are roughly orthogonal between the two task phases, and the decodings are predominantly of features of the present during the trial but features of the preceding trial during the ITI. These subspace distinctions are carried forward into sleep, where population activity is preferentially reactivated in post-training sleep but differently for activity from the trial and ITI subspaces. Our results suggest that the problem of interference when representing different states of the world is solved in mPfC by population activity occupying different subspaces for the world states, which can be independently decoded by downstream targets and independently addressed by upstream inputs.SIGNIFICANCE STATEMENT Activity in the medial prefrontal cortex plays a role in representing the current and past states of the world. We show that during a maze task, the activity of a single population in medial prefrontal cortex represents at least two different states of the world. These representations were sequential and sufficiently distinct that a downstream population could separately read out either state from that activity. Moreover, the activity representing different states is differently reactivated in sleep. Different world states can thus be represented in the same medial prefrontal cortex population but in such a way that prevents potentially catastrophic interference between them.     

Evaluating Visual Cues Modulates Their Representation in Mouse Visual and Cingulate Cortex

Choosing an action in response to visual cues relies on cognitive processes, such as perception, evaluation, and prediction, which can modulate visual representations even at early processing stages. In the mouse, it is challenging to isolate cognitive modulations of sensory signals because concurrent overt behavior patterns, such as locomotion, can also have brainwide influences. To address this challenge, we designed a task, in which head-fixed mice had to evaluate one of two visual cues. While their global shape signaled the opportunity to earn reward, the cues provided equivalent local stimulation to receptive fields of neurons in primary visual (V1) and anterior cingulate cortex (ACC). We found that mice evaluated these cues within few hundred milliseconds. During this period, ∼30% of V1 neurons became cue-selective, with preferences for either cue being balanced across the recorded population. This selectivity emerged in response to the behavioral demands because the same neurons could not discriminate the cues in sensory control measurements. In ACC, cue evaluation affected a similar fraction of neurons; emerging selectivity, however, was stronger than in V1, and preferences in the recorded population were biased toward the cue promising reward. Such a biased selectivity regime might allow the mouse to infer the promise of reward simply by the overall level of activity. Together, these experiments isolate the impact of task demands on neural responses in mouse cerebral cortex, and document distinct neural signatures of cue evaluation in V1 and ACC.SIGNIFICANCE STATEMENT Performing a cognitive task, such as evaluating visual cues, not only recruits frontal and parietal brain regions, but also modulates sensory processing stages. We trained mice to evaluate two visual cues, and show that, during this task, ∼30% of neurons recorded in V1 became selective for either cue, although they provided equivalent visual stimulation. We also show that, during cue evaluation, mice frequently move their eyes, even under head fixation, and that ignoring systematic differences in eye position can substantially obscure the modulations seen in V1 neurons. Finally, we document that modulations are stronger in ACC, and biased toward the reward-predicting cue, suggesting a transition in the neural representation of task-relevant information across processing stages in mouse cerebral cortex.     

Differentiating a Network of Executive Attention: Loreta Neurofeedback in Anterior Cingulate and Dorsolateral Prefrontal Cortices

Introduction: This study examines the differential effects of space-specific neuro-operant learning, utilizing low-resolution electromagnetic tomographic (LORETA) neurofeedback in three regions of training (ROTs), namely, the anterior cingulate gyrus (AC) and right and left dorsolateral prefrontal cortices (RPFC and LPFC respectively). Methods: This study was conducted with 14 nonclinical students with a mean age of 22. We utilized electrophysiological measurements and subtests of the WAIS-III for premeasures and postmeasures. Results: The data indicate that the AC shares a significant association with the RPFC and LPFC; however, each of the ROTs exhibits different cortical effects in all frequencies when trained exclusively. Discussion: LORETA neurofeedback (LNFB) appears to enhance the functioning and strengthening of networks of cortical units physiologically related to each ROT; moreover, significant changes are mapped for each frequency domain, showing the associations within this possible attentional network.     

Population Receptive Field Shapes in Early Visual Cortex Are Nearly Circular

The visual field region where a stimulus evokes a neural response is called the receptive field (RF). Analytical tools combined with functional MRI (fMRI) can estimate the RF of the population of neurons within a voxel. Circular population RF (pRF) methods accurately specify the central position of the pRF and provide some information about the spatial extent (diameter) of the RF. A number of investigators developed methods to further estimate the shape of the pRF, for example, whether the shape is more circular or elliptical. There is a report that there are many pRFs with highly elliptical pRFs in early visual cortex (V1–V3; Silson et al., 2018). Large aspect ratios (>2) are difficult to reconcile with the spatial scale of orientation columns or visual field map properties in early visual cortex. We started to replicate the experiments and found that the software used in the publication does not accurately estimate RF shape: it produces elliptical fits to circular ground-truth data. We analyzed an independent data set with a different software package that was validated over a specific range of measurement conditions, to show that in early visual cortex the aspect ratios are <2. Furthermore, current empirical and theoretical methods do not have enough precision to discriminate ellipses with aspect ratios of 1.5 from circles. Through simulation we identify methods for improving sensitivity that may estimate ellipses with smaller aspect ratios. The results we present are quantitatively consistent with prior assessments using other methodologies.SIGNIFICANCE STATEMENT We evaluated whether the shape of many population receptive fields (RFs) in early visual cortex is elliptical and differs substantially from circular. We evaluated two tools for estimating elliptical models of the pRF; one tool was valid over the measured compliance range. Using the validated tool, we found no evidence that confidently rejects circular fits to the pRF in visual field maps V1, V2, and V3. The new measurements and analyses are consistent with prior theoretical and experimental assessments in the literature.     

Visual Attention Modulates Glutamate-Glutamine Levels in Vestibular Cortex: Evidence from Magnetic Resonance Spectroscopy

Attending to a stimulus enhances the neuronal responses to it, while responses to nonattended stimuli are not enhanced and may even be suppressed. Although the neural mechanisms of response enhancement for attended stimuli have been intensely studied, the neural mechanisms underlying attentional suppression remain largely unknown. It is uncertain whether attention acts to suppress the processing in sensory cortical areas that would otherwise process the nonattended stimulus or the subcortical input to these cortical areas. Moreover, the neurochemical mechanisms inducing a reduction or suppression of neuronal responses to nonattended stimuli are as yet unknown. Here, we investigated how attention directed toward visual processing cross-modally acts to suppress vestibular responses in the human brain. By using functional magnetic resonance spectroscopy in a group of female and male subjects, we find that attention to visual motion downregulates in a load-dependent manner the concentration of excitatory neurotransmitter (glutamate and its precursor glutamine, referred to together as Glx) within the parietoinsular vestibular cortex (PIVC), a core cortical area of the vestibular system, while leaving the concentration of inhibitory neurotransmitter (GABA) in PIVC unchanged. This makes PIVC less responsive to excitatory thalamic vestibular input, as corroborated by functional magnetic resonance imaging. Together, our results suggest that attention acts to suppress the processing of nonattended sensory cues cortically by neurochemically rendering the core cortical area of the nonattended sensory modality less responsive to excitatory thalamic input.SIGNIFICANCE STATEMENT Here, we address a fundamental problem that has eluded attention research for decades, namely, how the brain ignores irrelevant stimuli. To date, three classes of solutions to this problem have been proposed: (1) enhancement of GABAergic interneuron activity in cortex, (2) downregulation of glutamatergic cell activity in cortex; and (3) downregulation of neural activity in thalamic projection areas, which would then provide the cortex with less input. Here, we use magnetic resonance spectroscopy in humans and find support for the second hypothesis, implying that attention to one sensory modality involves the suppression of irrelevant stimuli of another sensory modality by downregulating glutamate in the cortex.     

Temporally Specific Roles of Ventral Tegmental Area Projections to the Nucleus Accumbens and Prefrontal Cortex in Attention and Impulse Control

Deficits in impulse control and attention are prominent in the symptomatology of mental disorders such as attention deficit hyperactivity disorder (ADHD), substance addiction, schizophrenia, and bipolar disorder, yet the underlying mechanisms are incompletely understood. Frontostriatal structures, such as the nucleus accumbens (NAcb), the medial prefrontal cortex (mPFC), and their dopaminergic innervation from the ventral tegmental area (VTA) have been implicated in impulse control and attention. What remains unclear is how the temporal pattern of activity of these VTA projections contributes to these processes. Here, we optogenetically stimulated VTA dopamine (DA) cells, as well as VTA projections to the NAcb core (NAcbC), NAcb shell (NAcbS), and the mPFC in male rats performing the 5-choice serial reaction time task (5-CSRTT). Our data show that stimulation of VTA DA neurons, and VTA projections to the NAcbC and the mPFC immediately before presentation of the stimulus cue, impaired attention but spared impulse control. Importantly, in addition to reducing attention, activation of VTA-NAcbS also increased impulsivity when tested under a longer intertrial interval (ITI), to provoke impulsive behavior. Optogenetic stimulation at the beginning of the ITI only partially replicated these effects. In sum, our data show how attention and impulsivity are modulated by neuronal activity in distinct ascending output pathways from the VTA in a temporally specific manner. These findings increase our understanding of the intricate mechanisms by which mesocorticolimbic circuits contribute to cognition.SIGNIFICANCE STATEMENT Deficits in impulse control and attention are prominent in the symptomatology of several mental disorders, yet the brain mechanisms involved are incompletely understood. Since frontostriatal circuits have been implicated in impulse control and attention, we here examined the role of ascending projections from the midbrain ventral tegmental area (VTA) to the nucleus accumbens (NAcb) and prefrontal cortex (PFC). Using optogenetics to individually stimulate these projections with time-locked precision, we distinguished the role that each of these projections plays, in both impulse control and attention. As such, our study enhances our understanding of the neuronal circuitry that drives impulsive and attentive behavior.     

Dynamic Change of Endocannabinoid Signaling in the Medial Prefrontal Cortex Controls the Development of Depression After Neuropathic Pain

Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c-fos and in vivo electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI, and our results indicate that this resulted in a loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression.SIGNIFICANCE STATEMENT Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.     

Dysfunction of the Left Dorsolateral Prefrontal Cortex is Primarily Responsible for Impaired Attentional Processing in Schizophrenia

Objective

The results for finding the deficit in the anterior cingulate (ACC) in schizophrenic patients (SZ) have been inconsistent according to the studies that used different Stroop tasks, which is unlike the deficit in the dorsolateral prefrontal cortex (DLPFC). In order to explore for the core region that''s responsible for the selective attention deficit in SZ, we examined the results of a functional neuroimaging study, which involved the performance of the Stroop task using high or low prefrontal cortex related loads in SZ.

Methods

Ten schizophrenic patients and healthy controls (HC) received functional magnetic resonance imaging (fMRI) during a Short/Long-term latency Stroop task. The changes in the neural activity were determined in well-known Stroop related regions of interest (ROIs) that consisted of the DLPFC, ACC, the parietal lobule and in the whole brain regions for both the main and interaction effects of latency, and the results of the short-term and long-term latency Stroop conditions were compared.

Results

The response times for both the congruency and latency effects were more prolonged in the schizophrenics than in the HC. For the congruency effect, the schizophrenics showed significantly less activation in the same site of the left DLPFC in both the short-term and long-term latency conditions, as compared with the HC. For the latency effect, the regions of the left-side language network were over- or under-activated in the schizophrenics, as compared with the HC. Any interaction effect was not found for both the behavioral and fMRI results.

Conclusion

Our results indicate that the deficit in the left DLPFC is the core impairment of attentional processing in schizophrenics, regardless of other possible interactions such as the latency effect.     

Prefrontal unit activity during a color discrimination task with GO and NO-GO responses in the monkey

The activity of single neurons was recorded in the prefrontal cortex of monkeys performing a color discrimination GO and NO-GO task with a sequenced 3 visual stimuli (starting signal of a trial, discriminanda and command for response selection, respectively). A total of 161 units showed changes in their activity in association with at least one of the 4 events of the task (3 visual events and reward). Three patterns of activity change coupled to event onset (Type A, B and C) were found irrespective of the kind of events. Type A was a transient activity increase after event onset. Fifty-two units showed the Type A change. Three-fourths of them became active after one particular event, and the remaining one-fourth after more than one event. Type B was a gradual activity increase preceding event onset followed by a decrease after event onset. Sixty-five units showed the Type B change. In two-thirds of them, the activity changes occurred around one particular event, and in the remaining one-third around more than one event. Type C consisted of sustained activity between two different events. Eighty-three units showed the Type C change. This type of change was found in 5 different combinations of events. Four-fifthsof the 161 units showed one of 3 patterns, and the remaining one-fifth more than one of these patterns during different periods of a trial. It is suggested that Types A and B are involved in the information processing in relation to a particular event onset, and Type C provides a reference for distinction of events.     

Figure-Ground Segregation at Contours: a Neural Mechanism in the Visual Cortex of the Alert Monkey

An important task of vision is the segregation of figure and ground in situations of spatial occlusion. Psychophysical evidence suggests that the depth order at contours is defined early in visual processing. We have analysed this process in the visual cortex of the alert monkey. The animals were trained on a visual fixation task which reinforced foveal viewing. During periods of active visual fixation, we recorded the responses of single neurons in striate and prestriate cortex (areas V1, V2, and V3/V3A). The stimuli mimicked situations of spatial occlusion, usually a uniform light (or dark) rectangle overlaying a grating texture of opposite contrast. The direction of figure and ground at the borders of these rectangles was defined by the direction of the terminating grating lines (occlusion cues). Neuronal responses were analysed with respect to figure-ground direction and contrast polarity at such contours. Striate neurons often failed to respond to such stimuli, or were selective for contrast polarity; others were non-selective. Some neurons preferred a certain combination of figure-ground direction and contrast polarity. These neurons were rare both in striate and prestriate cortex. The majority of neurons signalled figure-ground direction independent of contrast polarity. These neurons were only found in prestriate cortex. We explain these responses in terms of a model which also explains neuronal signals of illusory contours. These results suggest that occlusion cues are used at an early level of processing to segregate figure and ground at contours.     

A Preferential Role for Ventromedial Prefrontal Cortex in Assessing “the Value of the Whole” in Multiattribute Object Evaluation

Everyday decision-making commonly involves assigning values to complex objects with multiple value-relevant attributes. Drawing on object recognition theories, we hypothesized two routes to multiattribute evaluation: assessing the value of the whole object based on holistic attribute configuration or summing individual attribute values. In two samples of healthy human male and female participants undergoing eye tracking and functional magnetic resonance imaging (fMRI) while evaluating novel pseudo objects, we found evidence for both forms of evaluation. Fixations to and transitions between attributes differed systematically when the value of pseudo objects was associated with individual attributes or attribute configurations. Ventromedial prefrontal cortex (vmPFC) and perirhinal cortex were engaged when configural processing was required. These results converge with our recent findings that individuals with vmPFC lesions were impaired in decisions requiring configural evaluation but not when evaluating the sum of the parts. This suggests that multiattribute decision-making engages distinct evaluation mechanisms relying on partially dissociable neural substrates, depending on the relationship between attributes and value.SIGNIFICANCE STATEMENT Decision neuroscience has only recently begun to address how multiple choice-relevant attributes are brought together during evaluation and choice among complex options. Object recognition research makes a crucial distinction between individual attribute and holistic/configural object processing, but how the brain evaluates attributes and whole objects remains unclear. Using fMRI and eye tracking, we found that the vmPFC and the perirhinal cortex contribute to value estimation specifically when value was related to whole objects, that is, predicted by the unique configuration of attributes and not when value was predicted by the sum of individual attribute values. This perspective on the interactions between subjective value and object processing mechanisms provides a novel bridge between the study of object recognition and reward-guided decision-making.     

Organization of visual cortex in the northern quoll, Dasyurus hallucatus: evidence for a homologue of the second visual area in marsupials

Two visual areas, V1 and V2 (first and second visual areas), appear to be present in the posterior neocortex of all eutherian mammals investigated so far. However, previous studies have not established whether an area homologous to V2 also exists in metatherian mammals (marsupials). Using electrophysiological techniques, we mapped the visual receptive fields of neurons in the striate and peristriate cortices of the northern quoll, an Australian marsupial. We found that neurons in a 2-mm-wide strip of cortex rostrolateral to V1 form a single, relatively simple representation of the complete contralateral hemifield. This area resembles V2 of eutherians in several respects: (i) neurons in the medial half of the peristriate area represent the lower visual quadrant, whereas those in the lateral half represent the upper visual quadrant; (ii) the vertical meridian of the visual field is represented adjacent to V1, while the visual field periphery is represented along the lateral and rostrolateral borders of the peristriate area; (iii) there is a marked anisotropy in the representation, with a larger magnification factor parallel to the V1 border than perpendicular to this border; and (iv) receptive fields of multiunit clusters in the peristriate cortex are much larger than those of cells in V1 at comparable eccentricities. The cortex immediately rostral and lateral to V2 did not respond to visual stimulation under our recording conditions. These results suggest that V1 and V2 together form a 'core' of homologous visual areas, likely to exist in all therian mammals.     

Evidence for a Slowly Inactivating K+ Current in Prefrontal Cortical Cells

The in vitro slice preparation of rat prefrontal cortical cells was used to analyse the presence and characteristics of a slowly inactivating outward current and its effect on the delayed integration of synaptic inputs. Pyramidal cells were identified as regular firing or bursting cells. In a fraction of these cells a depolarizing current pulse to –40 mV from a holding potential of –95 mV evoked the fast outward I_A current followed by a slower outward current (I_Ks) which inactivated slowly during the 3-s pulse. This slowly inactivating outward current was completely inactivated at holding potentials near –40 mV and was fully deinactivated by large hyperpolarizing pulses of 1 s duration. It was sensitive to micromolar concentrations of 4-aminopyridine and to 10 mM tetraethylammonium. In current clamp experiments, when the cells were maintained at –80 mV, they responded to subliminal depolarizing current pulses by a slow rising depolarization which reached threshold for spike firing after a delay of several seconds. This delay was considerably reduced either by maintaining the cell at less hyperpolarized potentials or by bath application of 40 μM 4-aminopyridine, or by repeated application of depolarizing pulses. The inactivation of I_Ks by the last procedure also led to plateau depolarization of the cell. These results suggest that the activation of the slowly inactivating outward current I_Ks can shunt excitatory inputs, preventing the cell from reaching spike threshold as long as it is not largely inactivated.     

Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia

Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.