Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells

Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here,weshowusingboth in vitroandin vivo recordingsfromthe rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to-Purkinje cell synapsescanalsoevokeincreases in intrinsic excitability. Thisformof intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction. Purkinje cell intrinsic plasticity resembles CA1 hippocampal pyramidal cell intrinsic plasticity in that it requires activity of protein kinase A(PKA) and casein kinase 2 (CK2) and is mediated by a downregulation of SK-type calcium-sensitive K conductances. In addition, Purkinje cell intrinsic plasticity similarly results in enhanced spine calcium signaling. However, there are fundamental differences: first, while in the hippocampus increases in excitability result in a higher probability for LTP induction, intrinsic plasticity in Purkinj

Learning intrinsic excitability in medium spiny neurons

We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parametrization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction.Comment: 20 pages, 8 figure

Relationship Between Learning-Related Synaptic and Intrinsic Plasticity Within Lateral Amygdala

A central question in neuroscience is to determine the mechanisms that govern formation, storage and modulation of memories. Determining these mechanisms would allow us to facilitate new memory formation as in the case of aging-related cognitive decline or weaken preexisting pathological memories such as traumatic memories and cue-induced drug craving. Pharmacological and genetic manipulation of intrinsic neuronal excitability has been demonstrated to impact the strength of memory formation, allocation of memories, and modulation of memories through retrieval and reconsolidation-dependent processes. In addition to experimental manipulations of intrinsic excitability, intrinsic plasticity, a change in neuronal intrinsic excitability, can be brought about by behavioral means such as learning. Indeed, learning-related intrinsic plasticity has been observed in many brain structures following acquisition of a variety of learning paradigms. Despite its ubiquitous nature, little is known about the functional significance of learning-induced intrinsic plasticity. Using the well-characterized lateral amygdala-dependent auditory fear conditioning as a behavioral paradigm, the current experiments investigated the time course and relationship between intrinsic and synaptic plasticity. We found that learning-related changes in amygdala intrinsic excitability were transient and were no longer evident 10 days following fear conditioning. We also found that fear learning related synaptic plasticity was evident up to 24hr following fear conditioning but not 4 days later. Finally, we demonstrate that the intrinsic excitability changes are evident in many of the same neurons that are undergoing synaptic facilitation immediately following fear conditioning. These data demonstrate that learning related intrinsic and synaptic changes are transient and co-localized to the same neurons. These data demonstrate that memory encoding neurons are more excitable, thus more likely to capture new memories for a time after the learning event

Neural mechanisms of social learning in the female mouse

Social interactions are often powerful drivers of learning. In female mice, mating creates a long-lasting sensory memory for the pheromones of the stud male that alters neuroendocrine responses to his chemosignals for many weeks. The cellular and synaptic correlates of pheromonal learning, however, remain unclear. We examined local circuit changes in the accessory olfactory bulb (AOB) using targeted ex vivo recordings of mating-activated neurons tagged with a fluorescent reporter. Imprinting led to striking plasticity in the intrinsic membrane excitability of projection neurons (mitral cells, MCs) that dramatically curtailed their responsiveness, suggesting a novel cellular substrate for pheromonal learning. Plasticity was selectively expressed in the MC ensembles activated by the stud male, consistent with formation of memories for specific individuals. Finally, MC excitability gained atypical activity-dependence whose slow dynamics strongly attenuated firing on timescales of several minutes. This unusual form of AOB plasticity may act to filter sustained or repetitive sensory signals.R21 DC013894 - NIDCD NIH HH

소뇌 퍼킨지 세포 내재적 흥분성의 활동-의존적 조절

학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2019. 2. 김상정.Learning rule has been thought to be implemented by activity-dependent modifications of synaptic function and neuronal excitability which contributing to maximization the information flow in the neural network. Since the sensory information is conveyed by forms of action potential (AP) firing, the plasticity of the intrinsic excitability (intrinsic plasticity) has been highlighted the computational feature of the brain. Given the cerebellar Purkinje cells (PCs) is the sole output neurons in the cerebellar cortex, coordination of the synaptic plasticity at the parallel fiber (PF) to PC synapses including long-term depression (LTD) and long-term potentiation (LTP) but also the intrinsic plasticity may play a essential role in information processing in the cerebellum. In this Dissertation, I have investigated several features of intrinsic plasticity in the cerebellar PCs in an activity-dependent manner and their cellular mechanism. Furthermore, the functional implications of the intrinsic plasticity in the cerebellum-dependent behavioral output are discussed. Firstly, I first cover the ion channels regulating the spiking activity of the cerebellar PCs and the cellular mechanisms of the plastic changes in excitability. Various ion channels indeed harmonize the cellular activity and shaping the optimal ranges of the neuronal excitability. Among the ion channels expressed in the cerebellar PCs, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to the non-Hebbian homeostatic intrinsic plasticity in the cerebellar PCs. Chronic activity-deprivation of PC activity caused the upregulation of agonist-independent activity of type 1 metabotropic glutamate receptor (mGluR1). The increased mGluR1 activity consequently enhanced the HCN channel current density through protein kinase A (PKA) pathway thereby downregulation of intrinsic excitability in PCs. In addition, the intrinsic excitability of PCs is found to be modulated by synaptic activity. Of interest, I investigated that the PF-PC LTD is accompanied by LTD of intrinsic excitability (LTD-IE). The LTD-IE indeed shared intracellular signal cascade for governing the synaptic LTD such as large amount of Ca2+ influx, mGluR1, protein kinase C (PKC) and Ca2+-calmodulin-dependent protein kinase II (CaMKII) activation. Interestingly, the LTD-IE reduced PC spike output without changes in patterns of synaptic integration and spike generation, suggesting that the intrinsic plasticity alters the quantity of information rather than the quality of information processing. In consistent, the LTD-IE was shown in the floccular PCs when the PF-PC LTD occurs. Notably, not only the synaptic LTD but also LTD-IE was found to be formed at the conditioned dendritic branch. Thus, synaptic plasticity could significantly affect to the neuronal net output through the synergistic coordination of synaptic and intrinsic plasticity in the dendrosomatic axis of the cerebellar PCs. In conclusion, the activity-dependent modulation of intrinsic excitability may contribute to dynamic tuning of the cerebellar PC output for appropriate signal transduction into the downstream neurons of the cerebellar PCs.생명체는 끊임없이 주변환경에 반응하여 행동을 수정하며 이러한 적응은 변화하는 환경에서 생존에 필수적이다. 소뇌-운동 학습은 대표적인 적응 행동의 예이다. 다양한 감각 신호들이 소뇌로 전달되어 처리된 후 소뇌 출력을 통해 운동 협응이 이루어진다. 이러한 소뇌-운동 학습 및 소뇌 기능 조절의 세포 생리학적 기전으로 소뇌 퍼킨지 세포의 시냅스 장기저하가 오랫동안 주목받았다. 퍼킨지 세포의 시냅스 장기저하가 나타나지 않는 유전자 변형 동물 모델들에서 소뇌-운동 학습이 정상적으로 일어나지 않는 현상이 관찰되었기 때문에 시냅스 장기저하 이론은 오랜 시간 소뇌-운동 학습의 기전으로 지지 받았다. 하지만 최근 10년 동안의 연구결과는 시냅스 장기저하만으로 소뇌-운동 학습 및 기능 조절을 설명할 수 없다고 반박한다. 특히 소뇌 퍼킨지 세포는 소뇌 피질로 전달된 감각신호를 처리하여 출력을 담당하는 유일한 신경세포이므로 운동 학습 상황에서 소뇌의 출력이 어떻게 조절되는지를 이해하는 것이 중요하게 인식되었다. 감각 신호가 신경 회로 내에서 전달될 때 활동 전압의 형태로 전달되기 때문에 활동 전압의 발생 빈도 및 패턴 조절 양상에 대한 이해는 소뇌 운동 학습의 기전을 밝히는 데에 중요하다. 본 박사학위 논문에서는 먼저 소뇌 퍼킨지 세포의 내재적 흥분성을 조절하는 여러가지 이온 통로들의 특성에 대해 정리하고 더 나아가 내재적 흥분성 가소성의 기전 및 생리학적 의의를 제시하였다. 소뇌 퍼킨지 세포의 흥분성은 활동-의존적 가소성을 보이는데, 시냅스의 활동이 아닌 소뇌 회로 활동성의 장기적인 변화에 대응하여 나타날 수 있다. 소뇌 회로의 활동을 2일 간의 tetrodotoxin (TTX, 1µM) 처리를 통해 저해하였을 때 과분극에 의해 발생하는 내향전류 (Ih) 증가를 통한 소뇌 퍼킨지 세포의 흥분성이 감소되는 것을 전기생리학적 기록을 통해 관찰하였다. 이러한 장기적인 소뇌 회로의 활동성 변화에 의한 퍼킨지 세포의 내재적 흥분성 감소의 세포생리학적 기전으로서 대사성 글루타메이트 수용체의 길항제-비의존적인 활동성 증가 및 그로 인한 PKA의 증가에 의해 발생함을 생화학 및 전기생리학적 방법을 통해 규명하였다. 이처럼 소뇌 퍼킨지 세포의 내재적 흥분성은 소뇌 회로 내에서 역동적으로 조절되어 소뇌 기능을 조절한다. 더 나아가 퍼킨지 세포의 흥분성 조절과 소뇌-기억형성과의 관계성을 검증하기 위해 소뇌-학습의 세포생리학적 기전으로 알려져있는 퍼킨지 세포 시냅스 장기저하 유도 후 흥분성의 변화를 관찰하였다. 흥미롭게도 퍼킨지 세포의 내재적 흥분성 역시 시냅스 가소성과 마찬가지로 평행섬유와 등반섬유의 활성을 통해 가소성을 보이는데 이 흥분성의 가소성은 대사성 글루타메이트 수용체, PKC 그리고 CaMKII와 같은 시냅스 장기 저하를 야기하는 세포 내 신호전달기전을 필요로 한다. 이러한 실험결과를 통해 시냅스 장기저하가 발생할 때 소뇌 퍼킨지 세포의 내재적 흥분성 역시 같이 감소하여 소뇌 운동 시 소뇌 피질의 출력이 크게 감소함을 예상할 수 있다. 실제로 소뇌 퍼킨지 세포의 신경가소성을 유도한 후 평행섬유를 자극하여 나타나는 퍼킨지 세포의 활동 전압 발생 빈도를 측정해 본 결과, 시냅스 장기저하와 흥분성의 장기저하가 함께 발생했을 때에만 소뇌 퍼킨지 세포의 출력이 유의미하게 감소하는 것을 관찰하였다. 특히 퍼킨지 세포의 활동-의존적 흥분성의 가소성은 시냅스 가소성과 마찬가지로 특정 수상돌기 가지 특이적으로 발생함을 관찰하였다. 이를 통해 퍼킨지 세포의 시냅스 가소성과 흥분성 가소성의 유기적인 연합을 통해 소뇌 퍼킨지 세포의 출력신호가 조절되어 소뇌-운동학습을 조절함을 알 수 있다. 결론적으로 본 박사학위 논문의 연구결과들은 소뇌 퍼킨지 세포의 출력은 퍼킨지 세포의 시냅스 가소성 혹은 흥분성의 조절과 비선형관계를 보이며 이러한 시냅스 가소성과 내재적 가소성의 시너지는 소뇌 정보 저장 능력을 극대화하여 소뇌 기능 조절 및 정보저장에 중요한 역할을 담당하고 있음을 제시한다.Preface Abstract General introduction Chapter 1. Summary of the previous literatures and further implication for physiological significance of the intrinsic plasticity in the cerebellar Purkinje cells Summary. 1.1 Ion channels and spiking activity of the cerebellar Purkinje cells 1.1.1 Voltage-gated Na+ channels 1.1.2 Voltage-gated K+ channels and Ca2+-activated K+ channels 1.2 Activity-dependent plasticity of intrinsic excitability through ion channel modulation 1.2.1 Activity-dependent plasticity of intrinsic. excitability through ion channel 1.2.2 Possible mechanisms for LTD-IE. 1.2.3 Upside down: to what extent does bidirectional intrinsic plasticity in. the cerebellar dependent-motor learning do? 1.3 The further implication of intrinsic plasticity in the memory circuits. Chapter 2. Type 1 metabotropic glutamate receptor mediates homeostatic control of intrinsic excitability through hyperpolarization-activated current in cerebellar Purkinje cells Introduction Material and Method Results 2.1 Chronic activity-deprivation reduces intrinsic excitability of the cerebellar. Purkinje cells 35 2.2 Homeostatic intrinsic plasticity of the cerebellar Purkinje cells is mediated activity-dependent modulation of Ih 2.3 Homeostatic intrinsic plasticity of the cerebellar Purkinje cells requires agonist-independent action of mGluR1 2.4 Homeostatic intrinsic plasticity of the cerebellar Purkinje cells is mediated. PKA activity Discussion Chapter 3. Long-Term Depression of Intrinsic Excitability Accompanied by Synaptic Depression in Cerebellar Purkinje Cells Introduction Material and Method Results 3.1 LTD of intrinsic excitability of PC accompanied by PF-PC LTD 3.2 LTD-IE has different developing kinetics from synaptic LTD 3.3 LTD-IE was not reversed by subsequent LTP-IE induction 3.4 The number of recruited synapses were not correlated to the magnitude of the neuronal 3.5 Information processing after LTD induction LTD-IE was not. reversed by subsequent LTP-IE induction 3.6 LTD-IE required the Ca2+-signal but not depended on the Ca2+-activated K+ channels Discussion Chapter 4. Synergies between synaptic depression and intrinsic plasticity of the cerebellar Purkinje cells determining the Purkinje cell output Introduction Material and Method Restuls 4.1 Timing rules of intrinsic plasticity of floccular PCs 87 4.2 Intrinsic plasticity shares intracellular signaling for PF-PC LTD 4.3 Conditioned PF branches contributing to robust reduction of spike output of the PCs 4.4 Sufficient changes in spiking output require both of plasticity, synaptic and. intrinsic plasticity 4.5 Supralinearity of spiking output coordination after induction of PC plasticity Discussion Bibliography Abstract in Korean AcknowledgementDocto

Biphasic Somatic A-Type K+ Channel Downregulation Mediates Intrinsic Plasticity in Hippocampal CA1 Pyramidal Neurons

Since its original description, the induction of synaptic long-term potentiation (LTP) has been known to be accompanied by a lasting increase in the intrinsic excitability (intrinsic plasticity) of hippocampal neurons. Recent evidence shows that dendritic excitability can be enhanced by an activity-dependent decrease in the activity of A-type K+ channels. In the present manuscript, we examined the role of A-type K+ channels in regulating intrinsic excitability of CA1 pyramidal neurons of the hippocampus after synapse-specific LTP induction. In electrophysiological recordings we found that LTP induced a potentiation of excitability which was accompanied by a two-phased change in A-type K+ channel activity recorded in nucleated patches from organotypic slices of rat hippocampus. Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K+ channel inactivation along with a progressive, long-lasting decrease in peak A-current density. Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity. These results suggest that two temporally distinct but overlapping mechanisms of A-channel downregulation together contribute to the plasticity of intrinsic excitability. Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling

Control over stress induces plasticity of individual prefrontal cortical neurons: A conductance-based neural simulation

Behavioral control over stressful stimuli induces resilience to future conditions when control is lacking. The medial prefrontal cortex(mPFC) is a critically important brain region required for plasticity of stress resilience. We found that control over stress induces plasticity of the intrinsic voltage-gated conductances of pyramidal neurons in the PFC. To gain insight into the underlying biophysical mechanisms of this plasticity we used the conductance- based neural simulation software tool, NEURON, to model the increase in membrane excitability associated with resilience to stress. A ball and stick multicompartment conductance-based model was used to realistically fit passive and active data traces from prototypical pyramidal neurons in neurons in rats with control over tail shock stress and those lacking control. The results indicate that the plasticity of membrane excitability associated with control over stress can be attributed to an increase in Na+ and Ca2+ T-type conductances and an increase in the leak conductance. Using simulated dendritic synaptic inputs we observed an increase in excitatory postsynaptic summation and amplification resulting in elevated action potential output. This realistic simulation suggests that control over stress enhances the output of the PFC and offers specific testable hypotheses to guide future electrophysiological mechanistic studies in animal models of resilience and vulnerability to stress

Microglial subtypes: diversity within the microglial community

Microglia are brain-resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single-cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or "subtype") displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.España, Ministerio de Ciencia, Innovación y Universidades FEDER y UE RTI2018-098645-B-10