Visual attention deficits in schizophrenia can arise from inhibitory dysfunction in thalamus or cortex

Schizophrenia is associated with diverse cognitive deficits, including disorders of attention-related oculomotor behavior. At the structural level, schizophrenia is associated with abnormal inhibitory control in the circuit linking cortex and thalamus. We developed a spiking neural network model that demonstrates how dysfunctional inhibition can degrade attentive gaze control. Our model revealed that perturbations of two functionally distinct classes of cortical inhibitory neurons, or of the inhibitory thalamic reticular nucleus, disrupted processing vital for sustained attention to a stimulus, leading to distractibility. Because perturbation at each circuit node led to comparable but qualitatively distinct disruptions in attentive tracking or fixation, our findings support the search for new eye movement metrics that may index distinct underlying neural defects. Moreover, because the cortico-thalamic circuit is a common motif across sensory, association, and motor systems, the model and extensions can be broadly applied to study normal function and the neural bases of other cognitive deficits in schizophrenia.R01 MH057414 - NIMH NIH HHS; R01 MH101209 - NIMH NIH HHS; R01 NS024760 - NINDS NIH HHSPublished versio

Analog VLSI-Based Modeling of the Primate Oculomotor System

One way to understand a neurobiological system is by building a simulacrum that replicates its behavior in real time using similar constraints. Analog very large-scale integrated (VLSI) electronic circuit technology provides such an enabling technology. We here describe a neuromorphic system that is part of a long-term effort to understand the primate oculomotor system. It requires both fast sensory processing and fast motor control to interact with the world. A one-dimensional hardware model of the primate eye has been built that simulates the physical dynamics of the biological system. It is driven by two different analog VLSI chips, one mimicking cortical visual processing for target selection and tracking and another modeling brain stem circuits that drive the eye muscles. Our oculomotor plant demonstrates both smooth pursuit movements, driven by a retinal velocity error signal, and saccadic eye movements, controlled by retinal position error, and can reproduce several behavioral, stimulation, lesion, and adaptation experiments performed on primates

Investigating Cognitive Control And Task Switching Using The Macaque Oculomotor System

Cognitive control is crucial to voluntary behaviour. It is required to select appropriate goals and guide behaviour to achieve the desired outcomes. Cognitive control is particularly important for the ability to adapt behaviour to changes in the external environment and internal goals, and to quickly switch between different tasks. Successful task switching involves a network of brain areas to select, maintain, implement, and execute the appropriate task. Uncovering the neural mechanisms of this goal-directed behaviour using lesions, functional neuroimaging, and neurophysiology studies is central to cognitive neuroscience. The oculomotor system provides a valuable framework for understanding the neural mechanisms of cognitive control, as it is anatomically and functionally well characterized. In this project, pro-saccade and anti-saccade tasks were used to investigate the contributions of oculomotor and cognitive brain areas to different stages of task processing. In Chapter 2, non-human primates performed cued and randomly interleaved pro-saccade and anti-saccade tasks while neural activity was recorded in the superior colliculus (SC). In Chapter 3, non-human primates performed cued and randomly interleaved pro-saccade and anti-saccade tasks while local field potential activity was recorded in the SC and reversible cryogenic deactivation was applied to the dorsolateral prefrontal cortex (DLPFC). In Chapter 4, non-human primates performed uncued and cued pro-saccade and anti-saccade switch tasks while reversible cryogenic deactivation was applied to the dorsal anterior cingulate cortex (dACC). The first study clarifies that macaque monkeys demonstrate similar error rate and reaction time switch costs to humans performing cued and randomly interleaved pro-saccade and anti-saccade tasks. These switch costs were associated with switch-related differences in stimulus-related activity in the SC that were resolved by the time of saccade onset. The second study shows that bilateral DLPFC deactivation decreases preparatory beta and gamma power in the superior colliculus. In addition, the correlation of gamma power with spike rate in the SC was attenuated by DLPFC deactivation. Lastly, bilateral dACC deactivation in the third study impairs anti-saccade performance and increases saccadic reaction times for pro-saccades and anti-saccades. Deactivation of the dACC also impairs the ability to integrate feedback from the previous trial. Overall, these findings suggest unique roles for the dACC, DLPFC, and SC in cognitive control and task switching. The dACC may monitor feedback to select the appropriate task and implement cognitive control, the DLPFC may maintain the current task-set and modulate the activity of other brain areas, and the SC may be modulated by task switching processes and contribute to the production of switch costs

Oculomotor learning revisited: a model of reinforcement learning in the basal ganglia incorporating an efference copy of motor actions

In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current “time” in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources

소뇌-의존적 운동 학습에 의해 유도된 소뇌 단백질 발현과 퍼킨지 세포 흥분성의 변화

학위논문(박사) -- 서울대학교대학원 : 의과대학 의과학과, 2021.8. 김상정.신경 과학에서 뇌의 고등 기능 중에 하나인 학습과 기억이 어떤 분자 혹은 세포 기전에 의해 매개되는가 하는 것은 흥미로는 주제이다. 이 문제를 해결하기 위한 다양한 실험적 접근들 중에서 야생형 동물의 뇌에서 학습 이후 나타나는 흔적을 추적하는 일은 근본적으로 널리 사용되어오는 접근법이다. 학위과정동안 나는 소뇌-의존적 운동 기억이 소뇌의 분자적 그리고 세포 수준에서 남기는 흔적들에 대한 탐구를 진행하였다. 먼저 제1장에서는 소뇌-의존적 학습이 소뇌의 분자적 수준에서 남기는 흔적을 찾기 위한 시도를 하였다. 소뇌는 운동의 강도를 적절하게 조정하여 운동 능력을 향상시키는데, 기존 연구에 따르면 운동의 강도가 조절되는 방향에 따라 각각 다른 종류의 세포 기전이 존재할 수 있다는 가능성이 제기되었다. 기억의 형성과 유지에 있어서 새로운 단백질의 합성이 필수적이라는 사실을 고려하여, 나는 운동의 강도 조절 측면에서 서로 다른 방향의 운동 학습이 소뇌에서의 서로 다른 단백질군의 발현을 유도할 것이라는 가설을 세웠다. 나는 운동의 강도가 강해지거나 약해지는 방향으로 일어나는 서로 다른 3 가지 종류의 소뇌-의존적 안구 운동 학습을 겪은 생쥐에서 학습이 끝난 후 1 시간과 24 시간이 지난 소뇌에서 단백질 발현 수준을 단백체 프로파일링을 사용하여 정량하였다. 실험의 결과, 3 가지 학습 패러다임 학습 후 1 시간과 24 시간의 각 소뇌에서 총 43 개의 차발현 단백질을 발견하였다. 또한, 기능적 온톨로지 분석을 사용하여 세 가지 안구 운동 학습 후 24 시간이 지난 소뇌에서 통제군에 비해 발현이 증가하거나 감소한 단백질 그룹을 확인하였는데, 이 결과는 세 가지 안구 운동 기억의 형성에 있어서 별개의 생물학적 경로가 관여할 수 있음을 제안한다. 가중 상관 네트워크 분석을 실시하여 안구 운동 기억 학습량과 상관 관계가 있는 단백질 그룹을 발견하였다. 마지막으로, 이 단백질 그룹 중 4 가지 단백질(Snca, Sncb, Cttn 및 Stmn1)을 선택하여 단백체 프로파일링의 결과를 웨스턴블롯분석으로 검증하였다. 이 연구는 세 가지 소뇌 의존적 운동 학습 패러다임과 관련된 종합적인 단백질 목록을 제공하는데, 연구의 결과는 각 학습 패러다임이 소뇌에서 서로 구별되는 단백질군의 발현을 유도할 수 있다는 점을 시사한다. 제2장에서는 앞서 언급한 3 가지 학습 패러다임 중에서 시운동 반응 적응 현상을 가지고 진행한 연구이다. 시운동 반응은 시야의 움직임이 발생하면 이를 추종하는 반사적 안구 운동으로 망막에 안정된 물체의 상이 맺힐 수 있도록 돕는 역할을 한다. 시운동 반응은 환경의 변화에 따라 그 반응의 정도가 조절되는 특성을 가지는데, 이런 적응 과정에 소뇌가 관여한다. 소뇌에 존재하는 여러 신경세포들 중, 퍼킨지 세포는 소뇌 피질로 전달된 여러 감각 정보들을 통합하고 소뇌의 유일한 출력을 담당하는 것으로 알려져 있는데, 이와 같이 시운동 반응을 통제하는 신경 회로 상 퍼킨지 세포의 중요성에도 불구하고 시운동 반응 적응 학습 상황에서 소뇌 퍼킨지 세포의 전기생리학적 특성을 밝히려는 시도는 여전히 부족한 것이 사실이다. 따라서 본 연구에서 나는 시운동 적응 학습 이후 소뇌 퍼킨지 세포에서의 내재적 및 스냅스 흥분성의 변화가 유발되는지 여부를 확인하였다. 통제군과 50분의 시운동 학습을 마친 학습군에서 소뇌를 각각 얻은 후 퍼킨지 세포에서 전기생리학적 특성을 분석한 결과, 나는 학습군의 퍼킨지 세포에서 통제군에 비해 세포내 탈분극 전류 주입에 반응하여 나타나는 활동 전위의 발화율이 줄어들고, 레오베이스 전류가 커졌음을 발견하였다. 또한, 시운동 적응 학습은 시냅스 전 신경 전달 물질 소포의 방출 확률을 감소시킴으로써 소뇌 평행섬유와 퍼킨지 세포 사이의 흥분성 시냅스 전달을 약화시켰다. 2장의 연구 결과를 종합하면, 시운동 적응 학습은 소뇌 퍼킨지 세포의 내재적 및 시냅스 수준 모두에서 신경 흥분성의 약화를 유발하는데, 이는 소뇌-의존적 안구 운동 학습을 매개하는 다중 가소성의 존재 가능성을 시사한다. 이 논문에서 나는 소뇌-의존적 운동 기억이 소뇌의 분자 그리고 세포 수준에서 남기는 기억 흔적을 찾기 위해 두 가지의 관찰 연구를 수행하였다. 탐구와 분석을 통해 찾은 후보 단백질과 신경 가소성은 운동 기억 형성 및 고착화 과정에 실제로 관여하는지 여부를 검증하는 후속 연구로 이어져 할 것이다. 결론적으로, 이 논문은 소뇌-의존적 운동 기억을 매개하지만 기존에 알려져 있지 않은 분자 또는 신경 가소성의 발견을 촉진하는 중요한 자원이 될 수 있을 것이다.One of the fundamental questions in neuroscience is how the brain encodes learning and memory processes at the molecular and cellular levels. Of the various approaches to resolve this question, it is useful to investigate the molecular or cellular traces that are formed in the brain after learning in wildtype animals. In this dissertation, I attempted to find traces of cerebellum-dependent motor memory at the molecular and cellular levels in the cerebellum. First, in chapter Ⅰ, I attempted to find the trace of cerebellum-dependent motor memory at the molecular level of the cerebellum. The cerebellum improves motor performance by adjusting the motor strength appropriately. According to previous studies, it has been suggested that distinct cellular mechanisms may exist depending on the direction in which the motor strength is adjusted. Given that de novo protein synthesis is essential in the formation and retention of memory in the brain, I hypothesized that motor learning in the opposite direction would induce a distinct pattern of protein expression in the cerebellum. I conducted quantitative proteomic profiling to compare the level of protein expression in the cerebellum at 1 and 24 h after training from mice that underwent different paradigms of cerebellum-dependent oculomotor learning from specific directional changes in motor gain. I quantified a total of 43 proteins that were significantly regulated in each of the three learning paradigms in the cerebellum at 1 and 24 h after learning. In addition, functional enrichment analysis identified protein groups that were differentially enriched or depleted in the cerebellum at 24 h after the three oculomotor learnings, suggesting that distinct biological pathways may be engaged in the formation of three oculomotor memories. Weighted correlation network analysis discovered groups of proteins significantly correlated with oculomotor memory. Finally, four proteins (Snca, Sncb, Cttn, and Stmn1) from the protein group correlated with the learning amount after oculomotor training were validated by Western blot. This study provides a comprehensive and unbiased list of proteins related to three cerebellum-dependent motor learning paradigms, suggesting the distinct nature of protein expression in the cerebellum for each learning paradigm. In chapter Ⅱ, I focused on the optokinetic response (OKR) learning among the three oculomotor paradigms mentioned above. The OKR is a reflexive eye movement evoked by a motion of the visual field to stabilize an image on the retina. The OKR is known to adapt its strength to cope with an environmental change throughout life. The cerebellum is well-known to participate in this oculomotor learning as an adaptive controller. In the adaptive controlling unit, the Purkinje cell (PC) is known to integrate multimodal sensory information in the cerebellar cortex as the sole output of the cerebellum. Despite the significance of PC in the neural circuit modulating OKR, the electrophysiological properties of PC in optokinetic learning have not been fully understood. Therefore, in this dissertation, I examined whether changes in the intrinsic and synaptic excitability of PC is induced in mice underwent 50 min of optokinetic learning. By utilizing the whole-cell patch-clamp recording, I compared the electrophysiological properties between the control and learned group, and found that the mean firing rate of PCs was decreased in response to intracellular depolarizing current injection and the rheobase current was increased in the learned group. In addition, I found that acute optokinetic learning induced a decrease in excitatory synaptic transmission at parallel fiber to PC synapse by reducing the presynaptic release probability. Taken together, optokinetic learning induces the suppressed neuronal excitability at both the intrinsic and synaptic factors of cerebellar PCs, suggesting the possibility of the occurrence of multiple plasticity governing cerebellum-dependent motor learning. In this dissertation, I conducted two independent observational studies to suggest possible molecular and cellular traces for cerebellum-dependent motor memory. Identified proteins and neural plasticity should lead us to further investigations to validate their roles in memory formation and consolidation. In conclusion, the discoveries in this dissertation would be a potentially important resource for discovering unknown molecules or plasticity mechanisms underlying cerebellum-dependent motor memory.Preface 1 Abstract 2 General Introduction 7 Chapter Ⅰ. Quantitative proteomics reveals distinct molecular signatures of different cerebellum-dependent learning paradigms 10 Introduction 11 Materials and Methods 13 Results 19 Discussion 39 Chapter Ⅱ. Suppressed intrinsic and synaptic excitability of cerebellar Purkinje cells following optokinetic learning in mice 45 Introduction 46 Materials and Methods 47 Results 51 Discussion 65 General Conclusion 69 Bibliography 70 Abstract in Korean 78박

Optogenetic perturbations reveal the dynamics of an oculomotor integrator

Many neural systems can store short-term information in persistently firing neurons. Such persistent activity is believed to be maintained by recurrent feedback among neurons. This hypothesis has been fleshed out in detail for the oculomotor integrator (OI) for which the so-called “line attractor” network model can explain a large set of observations. Here we show that there is a plethora of such models, distinguished by the relative strength of recurrent excitation and inhibition. In each model, the firing rates of the neurons relax toward the persistent activity states. The dynamics of relaxation can be quite different, however, and depend on the levels of recurrent excitation and inhibition. To identify the correct model, we directly measure these relaxation dynamics by performing optogenetic perturbations in the OI of zebrafish expressing halorhodopsin or channelrhodopsin. We show that instantaneous, inhibitory stimulations of the OI lead to persistent, centripetal eye position changes ipsilateral to the stimulation. Excitatory stimulations similarly cause centripetal eye position changes, yet only contralateral to the stimulation. These results show that the dynamics of the OI are organized around a central attractor state—the null position of the eyes—which stabilizes the system against random perturbations. Our results pose new constraints on the circuit connectivity of the system and provide new insights into the mechanisms underlying persistent activity

Implementation of a line attractor-based model of the gaze holding integrator using nonlinear spiking neuron models

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1996.Includes bibliographical references (leaves 30-31).by Ben Y. Reis.M.Eng

Eye velocity gain fields for visuo- motor coordinate transformations

’Gain-field-like’ tuning behavior is characterized by a modulation of the neuronal response depending on a certain variable, without changing the actual receptive field characteristics in relation to another variable. Eye position gain fields were first observed in area 7a of the posterior parietal cortex (PPC), where visually responsive neurons are modulated by ocular position. Analysis of artificial neural networks has shown that this type of tuning function might comprise the neuronal substrate for coordinate transformations. In this work, neuronal activity in the dorsal medial superior temporal area (MSTd) has been analyzed with an focus on it’s involvement in oculomotor control. MSTd is part of the extrastriate visual cortex and located in the PPC. Lesion studies suggested a participation of this cortical area in the control of eye movements. Inactivation of MSTd severely impairs the optokinetic response (OKR), which is an reflex-like kind of eye movement that compensates for motion of the whole visual scene. Using a novel, information-theory based approach for neuronal data analysis, we were able to identify those visual and eye movement related signals which were most correlated to the mean rate of spiking activity in MSTd neurons during optokinetic stimulation. In a majority of neurons firing rate was non-linearly related to a combination of retinal image velocity and eye velocity. The observed neuronal latency relative to these signals is in line with a system-level model of OKR, where an efference copy of the motor command signal is used to generate an internal estimate of the head-centered stimulus velocity signal. Tuning functions were obtained by using a probabilistic approach. In most MSTd neurons these functions exhibited gain-field-like shapes, with eye velocity modulating the visual response in a multiplicative manner. Population analysis revealed a large diversity of tuning forms including asymmetric and non-separable functions. The distribution of gain fields was almost identical to the predictions from a neural network model trained to perform the summation of image and eye velocity. These findings therefore strongly support the hypothesis of MSTd’s participation in the OKR control system by implementing the transformation from retinal image velocity to an estimate of stimulus velocity. In this sense, eye velocity gain fields constitute an intermediate step in transforming the eye-centered to a head-centered visual motion signal.Another aspect that was addressed in this work was the comparison of the irregularity of MSTd spiking activity during optokinetic response with the behavior during pure visual stimulation. The goal of this study was an evaluation of potential neuronal mechanisms underlying the observed gain field behavior. We found that both inter- and intra-trial variability were decreased with increasing retinal image velocity, but increased with eye velocity. This observation argues against a symmetrical integration of driving and modulating inputs. Instead, we propose an architecture where multiplicative gain modulation is achieved by simultaneous increase of excitatory and inhibitory background synaptic input. A conductance-based single-compartment model neuron was able to reproduce realistic gain modulation and the observed stimulus-dependence of neural variability, at the same time. In summary, this work leads to improved knowledge about MSTd’s role in visuomotor transformation by analyzing various functional and mechanistic aspects of eye velocity gain fields on a systems-, network-, and neuronal level

Aspects Of The Oculomotor System Of Callinectes Sapidus

An isolated perfused preparation was developed for the study of several aspects of the oculomotor system of the blue crab, Callinectes sapidus. The system for eyestalk rotation was investigated on an extracellular level. Two antagonistic pairs of muscles under visual and statocyst control were found to be responsible for stabilization and rotation of the eyestalk. The primary sensory input to the muscles appears to be from the statocysts, with both static position sense and dynamic acceleration components influencing the motor response. Two sensory feedback systems from mechanoreceptive hairs were found which influence the response of the eye stalks to statocyst input. The function of one system appears to be to allow· the animal to differentiate between statocyst stimulation caused by whole body movement and that caused by movement of the basal segment of the antennule in which the statocyst is lodged. The second negative feedback system appears to have a multiple function. It is believed to function to null out the tonic excitatory position sense input from the statocysts when it is necessary for the eye to make a movement which is contrary to the position sense input as, for example, when the animal is following a visual target whose direction is opposite to that of the statocyst drive. It also produces reciprocal inhibition of the antagonist muscle. In addition, this system may be responsible for the incomplete compensation seen in compensatory eye movements made in response to pitch of the body. A preliminary survey of the oculomotor neurons and interneurons in the cerebral ganglion established the potential of this ganglion for intracellular recording from components of the oculomotor system. Recordings were made from both motorneurons and interneurons. The recording from interneurone of the oculomotor system was particularly good. Eye movements could be elicted in response to visual and tactile stimuli while recording from the ganglion. The preparation appears ·to be an excellent system in which to undertake an extensive analysis of intracellular events in the neuronal network underlying stereotyped eye movements and could lead to an understanding of the neuronal basis for such movements. In the course of the above work on the oculomotor system, same observations were made on the cor frontale which controls the blood pressure to the cerebral system. The cor frontale had been thought to function as a heart regulating blood flow to the cerebral ganglion. It appears from this work that the cor frontale may not function as a heart but rather as a resistive mechanism for regulation of the blood pressure, more like the vertebrate arteriole. Furthermore, the function of this organ may not be to protect the flow to the cerebral ganglion but rather to insure the constancy of the pressure in the peripheral sensory, integrative and oculomotor apparatus of the eyecup