Selective Disinhibition Research Articles

Status epilepticus induces chronic silencing of burster and dominance of regular firing neurons during sharp wave-ripples in the mouse subiculum

Sharp wave-ripples (SWRs) are hippocampal oscillations associated with memory consolidation. The subiculum, as the hippocampal output structure, ensures that hippocampal memory representations are transferred correctly to the consolidating neocortical regions. Because patients with temporal lobe epilepsy often develop memory deficits, we hypothesized that epileptic networks may disrupt subicular SWRs. We therefore investigated the impact of experimentally induced status epilepticus (SE) on subicular SWRs and contributing pyramidal neurons using electrophysiological recordings in mouse hippocampal slices. Subicular SWRs expressed hyperexcitable features post-SE, including increased ripple and unit activity. While regular firing neurons normally remain silent during SWRs, selective disinhibition recruited more regular firing neurons for action potential generation during SWRs post-SE. By contrast, burster neurons generated fewer action potential bursts during SWRs post-SE. Furthermore, altered timing of postsynaptic and action potentials suggested distorted neuronal recruitment during SWRs. Distorted subicular SWRs may therefore impair information processing and memory consolidation in epilepsy.

Visual Deprivation Selectively Reduces Thalamic Reticular Nucleus-Mediated Inhibition of the Auditory Thalamus in Adults.

Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain.SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.

High-frequency oscillations and sequence generation in two-population models of hippocampal region CA1.

Hippocampal sharp wave/ripple oscillations are a prominent pattern of collective activity, which consists of a strong overall increase of activity with superimposed (140 − 200 Hz) ripple oscillations. Despite its prominence and its experimentally demonstrated importance for memory consolidation, the mechanisms underlying its generation are to date not understood. Several models assume that recurrent networks of inhibitory cells alone can explain the generation and main characteristics of the ripple oscillations. Recent experiments, however, indicate that in addition to inhibitory basket cells, the pattern requires in vivo the activity of the local population of excitatory pyramidal cells. Here, we study a model for networks in the hippocampal region CA1 incorporating such a local excitatory population of pyramidal neurons. We start by investigating its ability to generate ripple oscillations using extensive simulations. Using biologically plausible parameters, we find that short pulses of external excitation triggering excitatory cell spiking are required for sharp/wave ripple generation with oscillation patterns similar to in vivo observations. Our model has plausible values for single neuron, synapse and connectivity parameters, random connectivity and no strong feedforward drive to the inhibitory population. Specifically, whereas temporally broad excitation can lead to high-frequency oscillations in the ripple range, sparse pyramidal cell activity is only obtained with pulse-like external CA3 excitation. Further simulations indicate that such short pulses could originate from dendritic spikes in the apical or basal dendrites of CA1 pyramidal cells, which are triggered by coincident spike arrivals from hippocampal region CA3. Finally we show that replay of sequences by pyramidal neurons and ripple oscillations can arise intrinsically in CA1 due to structured connectivity that gives rise to alternating excitatory pulse and inhibitory gap coding; the latter denotes phases of silence in specific basket cell groups, which induce selective disinhibition of groups of pyramidal neurons. This general mechanism for sequence generation leads to sparse pyramidal cell and dense basket cell spiking, does not rely on synfire chain-like feedforward excitation and may be relevant for other brain regions as well.

Multiple neuronal circuits for variable object–action choices based on short- and long-term memories

At each time in our life, we choose one or few behaviors, while suppressing many other behaviors. This is the basic mechanism in the basal ganglia, which is done by tonic inhibition and selective disinhibition. Dysfunctions of the basal ganglia then cause 2 types of disorders (difficulty in initiating necessary actions and difficulty in suppressing unnecessary actions) that occur in Parkinson’s disease. The basal ganglia generate such opposite outcomes through parallel circuits: The direct pathway for initiation and indirect pathway for suppression. Importantly, the direct pathway processes good information and the indirect pathway processes bad information, which enables the choice of good behavior and the rejection of bad behavior. This is mainly enabled by dopaminergic inputs to these circuits. However, the value judgment is complex because the world is complex. Sometimes, the value must be based on recent events, thus is based on short-term memories. Or, the value must be based on historical events, thus is based on long-term memories. Such memory-based value judgment is generated by another parallel circuit originating from the caudate head and caudate tail. These circuit-information mechanisms allow other brain areas (e.g., prefrontal cortex) to contribute to decisions by sending information to these basal ganglia circuits. Moreover, the basal ganglia mechanisms (i.e., what to choose) are associated with cerebellum mechanisms (i.e., when to choose). Overall, multiple levels of parallel circuits in and around the basal ganglia are essential for coordinated behaviors. Understanding these circuits is useful for creating clinical treatments of disorders resulting from the failure of these circuits.

Calvarial osteoblast gene expression in patients with craniosynostosis leads to novel polygenic mouse model.

Craniosynostosis is the premature fusion of the sutures of the calvaria and is principally designated as being either syndromic (demonstrating characteristic extracranial malformations) or non-syndromic. While many forms of syndromic craniosynostosis are known to be caused by specific mutations, the genetic etiology of non-syndromic, single-suture craniosynostosis (SSC) is poorly understood. Based on the low recurrence rate (4–7%) and the fact that recurrent mutations have not been identified for most cases of SSC, we propose that some cases of isolated, single suture craniosynostosis may be polygenic. Previous work in our lab identified a disproportionately high number of rare and novel gain-of-function IGF1R variants in patients with SSC as compared to controls. Building upon this result, we used expression array data from calvarial osteoblasts isolated from infants with and without SSC to ascertain correlations between high IGF1 expression and expression of other osteogenic genes of interest. We identified a positive correlation between increased expression of IGF1 and RUNX2, a gene known to cause SSC with increased gene dosage. Subsequent phosphorylation assays revealed that osteoblast cell lines from cases with high IGF1 expression demonstrated inhibition of GSK3β, a serine/threonine kinase known to inhibit RUNX2, thus activating osteogenesis through the IRS1-mediated Akt pathway. With these findings, we have utilized established mouse strains to examine a novel model of polygenic inheritance (a phenotype influenced by more than one gene) of SSC. Compound heterozygous mice with selective disinhibition of RUNX2 and either overexpression of IGF1 or loss of function of GSK3β demonstrated an increase in the frequency and severity of synostosis as compared to mice with the RUNX2 disinhibition alone. These polygenic mouse models reinforce, in-vivo, that the combination of activation of the IGF1 pathway and disinhibition of the RUNX2 pathway leads to an increased risk of developing craniosynostosis and serves as a model of human SSC.

Selective sensorimotor modulation operates during cognitive representation of movement

Before movement onset, during the reaction time, excitability of M1 is selectively modulated by somatosensory inputs, only in the movement-related muscle. If a similar mechanism operates before the onset of mental movements, then somatosensory afferent inputs are exploited during cognitive representation of movement. We assessed sensorimotor modulation through short latency afferent inhibition (SAI) paradigm before the onset of executed and imagined movements.Participants performed or imagined an abduction of index or little finger, in response to an acoustic signal. SAI was evaluated between a Warning and a Go signal and 100 ms after the Go signal, before the real or expected EMG activity. Results showed a reduction of SAI after the Go signal, in the movement-related muscle, during motor imagery as well as movement execution. There was a positive correlation between the individual degree of sensorimotor modulation during executed and mental movements and between the sensorimotor modulation during mental movements and motor imagery ability. Sensorimotor modulation operates during the cognitive representation of movement with selective disinhibition of the cortical representation of the muscle involved in the task. Sensorimotor modulation mechanisms prior to mental and executed movements likely share overlapping circuits.

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.

Biomimetic race model of the loop between the superior colliculus and the basal ganglia: Subcortical selection of saccade targets

The superior colliculus, a laminar structure involved in the retinotopic mapping of the visual field, plays a cardinal role in several cortical and subcortical pathways of the saccadic system. Although the selection of saccade targets has long been thought to be mainly the product of cortical processes, a growing body of evidence hints at the implication of the superior colliculus in selection processes independent from cortical inputs, capable of producing saccades at latencies incompatible with the cortical pathways. This selection ability could be produced firstly by the lateral connections between the neurons of its maps, and secondly by its interactions with the midbrain basal ganglia, already renowned for their role in decision making.We propose a biomimetic population-coded race model of selection based on a dynamic tecto-basal loop that reproduces the observed ability of the superior colliculus to stochastically select between similar stimuli. Our model’s selection accuracy depends on the discriminability of the target and the distractors. Our model also offers an explanation for the phenomenon of Remote Distractor Effect based on the lateral connectivity within the basal ganglia circuitry rather than on lateral inhibitions within the collicular maps. Finally, we propose a role for the intermediate layers of the superior colliculus, as stochastic integrators dynamically gated by the selective disinhibition of the basal ganglia channels that is consistent with the recorded activity profiles of these neurons.

Chapter 19 - Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders

Progressive neurodegenerative disorders are devastating diseases with often fatal outcomes. Lower urinary tract symptoms (LUTS) add to morbidity and increase the risk of becoming dependent on the help of others (e.g., nursing-home referral). In Parkinson's disease (PD), the specific loss of dopaminergic neurons in the substantia nigra and possibly also in the ventral tegmental area induces loss of neurogenic bladder control through dysfunction of a complex network in which selective disinhibition of bladder reflexes is lost. In PD, more than 60% of patients have troublesome bladder symptoms, and 30% experience incontinence, though not daily. In atypical parkinsonism, including multiple system atrophy, LUTS are highly prevalent, and the onset of LUTS in comparison to other autonomic symptoms and motor symptoms may serve as a diagnostic marker. Less is known about the pathophysiology of incontinence in Alzheimer's disease, but higher cognitive function including attention and self-management may play a role. Incontinence is a major risk factor for loss of independence. The complex pathophysiologic mechanisms of neurodegenerative disorders and hence complex symptoms play important roles in LUTS and patient quality of life. Nocturia, incontinence, and urgency as well as poor bladder emptying are the most common symptoms. These symptoms may interact with the core symptoms of the disorders, increasing the risk of incontinence and infection. In rarer neurogenerative disorder LUTS may be present, most commonly in disorders with spinal cord involvement. The systematic and careful tracking of symptoms, evaluation using non-invasive techniques, and conservative management including pharmacologic treatments can often markedly improve the lives of patients and their caregivers.

Selective disinhibition: A unified neural mechanism for predictive and post hoc attentional selection

The natural world presents us with a rich and ever-changing sensory landscape containing diverse stimuli that constantly compete for representation in the brain. When the brain selects a stimulus as the highest priority for attention, it differentially enhances the representation of the selected, “target” stimulus and suppresses the processing of other, distracting stimuli. A stimulus may be selected for attention while it is still present in the visual scene (predictive selection) or after it has vanished (post hoc selection). We present a biologically inspired computational model that accounts for the prioritized processing of information about targets that are selected for attention either predictively or post hoc. Central to the model is the neurobiological mechanism of “selective disinhibition” – the selective suppression of inhibition of the representation of the target stimulus. We demonstrate that this mechanism explains major neurophysiological hallmarks of selective attention, including multiplicative neural gain, increased inter-trial reliability (decreased variability), and reduced noise correlations. The same mechanism also reproduces key behavioral hallmarks associated with target-distracter interactions. Selective disinhibition exhibits several distinguishing and advantageous features over alternative mechanisms for implementing target selection, and is capable of explaining the effects of selective attention over a broad range of real-world conditions, involving both predictive and post hoc biasing of sensory competition and decisions.

Functional properties of the basal ganglia's re-entrant loop architecture: selection and reinforcement

Multifunctional agents with limited motor resources must decide what actions will best ensure their survival. Moreover, given that in an unpredictable world things don't always work out, considerable advantage is to be gained by learning from experience - instrumental behaviour that maximises reward and minimises punishment. In this review we will argue that the re-entrant looped architecture of the basal ganglia represents biological solutions to these fundamental behavioural problems of selection and reinforcement. A potential solution to the selection problem is provided for by selective disinhibition within the parallel loop architecture that connects the basal ganglia with external neural structures. The relay points within these loops permit the signals of a particular channel to be modified by external influences. In part, these influences have the capacity to modify overall selections so that the probability of re-selecting reinforced behaviours in the future is altered. This is the basic process of instrumental learning, which we suggest decomposes into two sub-problems for the agent: (i) learning which external events it causes to happen and learning precisely what it is doing that is causal; and (ii) having determined agency and discovered novel action-outcome routines, how best to exploit this knowledge to maximise future reward acquisitions. Considerations of connectional architecture and signal timing suggest that the short-latency, sensory-evoked dopamine response, which can modulate the re-entrant loop structure within the basal ganglia, is ideally suited to reinforce the determination of agency and the discovery of novel actions. Alternatively, recent studies showing that presence or absence of reward can selectively modulate the magnitude of signals in structures providing input signals to the basal ganglia, offer an alternative mechanism for biasing selection within the re-entrant loop architecture. We suggest that this mechanism may be better suited to ensure the prioritisation of inputs associated with reward.

Alcohol Consumption, Alcoholics Anonymous Membership, and Homicide Mortality Rates in Ontario 1968 to 1991

Research has shown a strong link between alcohol use and a variety of problems, including violence. Parker and colleagues have presented a selective disinhibition theory for the link between alcohol use and homicide (and other violence) that posits a causal relationship that is also influenced by other situational and contextual factors. This model is particularly well suited for aggregate-level investigations. In this study, we examine the impact of alcohol factors, including consumption measures and Alcoholics Anonymous (AA) membership rates, on homicide mortality rates in Ontario, and test predictions derived from the selective disinhibition model. Time series analyses with ARIMA modeling were applied to total, male, and female homicide rates in Ontario between 1968 and 1991. The analyses performed included total alcohol consumption, spirits consumption, beer consumption, and wine consumption. Missing AA membership data were interpolated with cubic splines. For the total population and males, homicide rates were significantly and positively related to total alcohol consumption and to the consumption of beer and spirits. They were also negatively related to AA membership rates in the analyses involving spirits and wine and positively related to unemployment rates in the analyses involving beer, wine, and total alcohol. Among females, none of the measures were significant predictors of homicide mortality rates. These data provide important support for the selective disinhibition model and confirm important relationships between per capita consumption measures and homicide mortality rates, especially among males, seen in other studies. Additionally, the results for AA membership rates are consistent with the hypothesis that AA membership and treatment for misuse of alcohol can exert beneficial effects observable at the population level.

Excitatory and Feed-Forward Inhibitory Hippocampal Synapses Work Synergistically as an Adaptive Filter of Natural Spike Trains

Short-term synaptic plasticity (STP) is an important mechanism for modifying neural circuits during computation. Although STP is much studied, its role in the processing of complex natural spike patterns is unknown. Here we analyze the responses of excitatory and inhibitory hippocampal synapses to natural spike trains at near-physiological temperatures. Our results show that excitatory and inhibitory synapses express complementary sets of STP components that selectively change synaptic strength during epochs of high-frequency discharge associated with hippocampal place fields. In both types of synapses, synaptic strength rapidly alternates between a near-constant level during low activity and another near-constant, but elevated (for excitatory synapses) or reduced (for inhibitory synapses) level during high-frequency epochs. These history-dependent changes in synaptic strength are largely independent of the particular temporal pattern within the discharges, and occur concomitantly in the two types of synapses. When excitatory and feed-forward inhibitory synapses are co-activated within the hippocampal feed-forward circuit unit, the net effect of their complementary STP is an additional increase in the gain of excitatory synapses during high-frequency discharges via selective disinhibition. Thus, excitatory and feed-forward inhibitory hippocampal synapses in vitro act synergistically as an adaptive filter that operates in a switch-like manner and is selective for high-frequency epochs.

Neurophysiological events during the head critical period for prothoracicotropic hormone release in fourth-instar larvae of Manduca sexta

The initiation of larval moulting in the tobacco hornworm, Manduca sexta, involves an endocrine cascade that begins with the release of the cerebral prothoracicotropic hormone (PTTH) from the retrocerebral corpora allata. During the fourth larva instar of Manduca when the gated release of PTTH occurs, the in situ electrical activity of the nervi corporis cardiaci (NCC I + II), the paired nerve trunks from the brain that innervate the corpora cardiaca and more distal corpora allata, undergoes a distinct change in firing pattern. The initial change in pattern, from a steady firing, was a brief, intense burst of relatively large units followed by a short period (3–10 min) of completely suppressed activity. Next, bursting activity of several different units resumed, and depending upon the preparation, this event was either long or short in duration. This unique bursting pattern occurred at about the head critical period for PTTH release and was expressed by the brain-corpus cardiacum-allatum both in situ and in vitro. The complexity of the action potential patterns suggests that a variety of neurosecretory cell types may be involved in a coordinated, transient inhibition of electrical activity of the NCC I + II that is followed by selective disinhibition of a specific set of cerebral neurones that, based upon the release of PTTH from the corpus cardiacum-allatum preparations, culminates in PTTH release. That this neurophysiological event occurs at a precise time and occurs in vitro suggests that a pattern generator for the unique bursting firing and a clock mechanism controlling this event reside within the brain-corpus cardiacum-allatum. The significance of these results in relation to the neuroendocrinology of larval mounting is discussed.

A neural systems theory of schizophrenia and tardive dyskinesia

Some systems ideas applied to individual persons are used to try to explain symptoms of schizophrenia and a syndrome of uncontrolled fragments of movement which sometimes occurs as a side effect of chronic, antipsychotic drug therapy. The behavior of normal organisms may be conceptualized in three echelons of control, with each successively higher echelon organizing, by selective disinhibition, semiautonomous, spontaneous fragments of activity which comprise the next lower echelon. It is hypothesized that schizophrenia involves a deficiency of inhibition by the frontal cortex, first echelon, on the corpus striatum, second echelon. This results first in insufficiently integrated fragments of behavior, and second in premature associative linkages among active elements. First echelon control develops as a normal person matures and gradually loses some of the playful activities of childhood. It is hypothesized that by disrupting certain aspects of activity in the corpus striatum, neuroleptic drugs reduce schizophrenic symptoms but also reduce the capacity of the second echelon to inhibit and integrate the smaller behavioral fragments wired into lower parts of the brain, third echelon. This results in uncontrolled movements. Though many researchers already favor the hypothesis that neuroleptic drugs act on the corpus striatum, the broader theory presented here is new and depends in large part on general living systems considerations. Emphasis is on conceptual decomposition of the integrated behavior of a whole organism into less complex subsystems. Individually, these have neither too much nor too little complexity to yield a plausible model. Some experimental predictions and predictions about possible therapies are made from the theory.