Subcortical Neurons Research Articles

The functional roles of neural remapping in cortex.

Remapping is a property of some cortical and subcortical neurons that update their responses around the time of an eye movement to account for the shift of stimuli on the retina due to the saccade. Physiologically, remapping is traditionally tested by briefly presenting a single stimulus around the time of the saccade and looking at the onset of the response and the locations in space to which the neuron is responsive. Here we suggest that a better way to understand the functional role of remapping is to look at the time at which the neural signal emerges when saccades are made across a stable scene. Based on data obtained using this approach, we suggest that remapping in the lateral intraparietal area is sufficient to play a role in maintaining visual stability across saccades, whereas in the frontal eye field, remapped activity carries information that affects future saccadic choices and, in a separate subset of neurons, is used to maintain a map of locations in the scene that have been previously fixated.

PERENITY OF THE NEW ANATOMIC CONCEPT “VENTRAL STRIATOPALLIDAL SYSTEM”. PSYCHOPATHOLOGICAL IMPLICATIONS

Diversification of research microanatomic methods of subcortical neuron structures has led to the re- structuring of the classical concept of basal ganglia and the working out of a new anatomic concept of ventral striatopallidal system. Macroanatomic visualization and evaluation of subsystems and structures of this new system are pioneering issues in the description and topography of the basal forebrain. The authors’ aim – based on our macroanatomic experience – is at debating several issues associated to the progress in deciphering subcortical neuronal structures which generated dilemmas regarding their naming and evaluation. We based our study on post-mortem human biological samples, with the observation of the ethics and deontology of research. The study was carried out on four human brains free from acute or chronic lesions, that were taken from two men and two women aged between 55 and 65. They were analyzed after pre-fixation in solution 10% formaldehyde for 10 days and post-fixation in solution 5% formaldehyde for 6 months. Evaluation of location and subsystems’ relations within the structures of the ventral striatopallidal system were based on the macroscopic anatomic analysis of serial sections carried out both on the brain and forebrain. We noticed several issues associated to: choosing the references for serial sections on the brain and forebrain; identification of the delimitations of subsystems from the dorsal striatum and the ventral striatum on the one hand and the structures in the ventral pallidum, on the other; the paths and the relations of the “extensions” originating in the dorsal striatum and in the amygdaloid body; anatomic and/or functional criteria of grouping the structure in the basal nuclei. The new concept of “ventral striatopallidal system” implies extra information on the integration of neuronal structure within the Limbic – Motor Interface.

Noise-Sensitive But More Precise Subcortical Representations Coexist with Robust Cortical Encoding of Natural Vocalizations.

Humans and animals maintain accurate sound discrimination in the presence of loud sources of background noise. It is commonly assumed that this ability relies on the robustness of auditory cortex responses. However, only a few attempts have been made to characterize neural discrimination of communication sounds masked by noise at each stage of the auditory system and to quantify the noise effects on the neuronal discrimination in terms of alterations in amplitude modulations. Here, we measured neural discrimination between communication sounds masked by a vocalization-shaped stationary noise from multiunit responses recorded in the cochlear nucleus, inferior colliculus, auditory thalamus, and primary and secondary auditory cortex at several signal-to-noise ratios (SNRs) in anesthetized male or female guinea pigs. Masking noise decreased sound discrimination of neuronal populations in each auditory structure, but collicular and thalamic populations showed better performance than cortical populations at each SNR. In contrast, in each auditory structure, discrimination by neuronal populations was slightly decreased when tone-vocoded vocalizations were tested. These results shed new light on the specific contributions of subcortical structures to robust sound encoding, and suggest that the distortion of slow amplitude modulation cues conveyed by communication sounds is one of the factors constraining the neuronal discrimination in subcortical and cortical levels.SIGNIFICANCE STATEMENT Dissecting how auditory neurons discriminate communication sounds in noise is a major goal in auditory neuroscience. Robust sound coding in noise is often viewed as a specific property of cortical networks, although this remains to be demonstrated. Here, we tested the discrimination performance of neuronal populations at five levels of the auditory system in response to conspecific vocalizations masked by noise. In each acoustic condition, subcortical neurons better discriminated target vocalizations than cortical ones and in each structure, the reduction in discrimination performance was related to the reduction in slow amplitude modulation cues.

Extraction of Distinct Neuronal Cell Types from within a Genetically Continuous Population

Single-cell transcriptomics of neocortical neurons have revealed more than 100 clusters corresponding to putative cell types. For inhibitory and subcortical projection neurons (SCPNs), there is a strong concordance between clusters and anatomical descriptions of cell types. In contrast, cortico-cortical projection neurons (CCPNs) separate into surprisingly few transcriptomic clusters, despite their diverse anatomical projection types. We used projection-dependent single-cell transcriptomic analyses and monosynaptic rabies tracing to compare mouse primary visual cortex CCPNs projecting to different higher visual areas. We find that layer 2/3 CCPNs with different anatomical projections differ systematically in their gene expressions, despite forming only a single genetic cluster. Furthermore, these neurons receive feedback selectively from the same areas to which they project. These findings demonstrate that gene-expression analysis in isolation is insufficient to identify neuron types and have important implications for understanding the functional role of cortical feedback circuits.

Extraretinal Spike Normalization in Retinal Ganglion Cell Axons.

Spike conduction velocity characteristically differs between myelinated and unmyelinated axons. Here we test whether spikes of myelinated and unmyelinated paths differ in other respects by measuring rat retinal ganglion cell (RGC) spike duration in the intraretinal, unmyelinated nerve fiber layer and the extraretinal, myelinated optic nerve and optic chiasm. We find that rapid spike firing and illumination broaden spikes in intraretinal axons but not in extraretinal axons. RGC axons thus initiate spikes intraretinally and normalize spike duration extraretinally. Additionally, we analyze spikes that were recorded in a previous study of rhesus macaque retinogeniculate transmission and find that rapid spike firing does not broaden spikes in optic tract. The spike normalization we find reduces the number of spike properties that can change during RGC light responses. However, this is not because identical spikes fire in all axons. Instead, our recordings show that different subtypes of RGC generate axonal spikes of different durations and that the differences resemble spike duration increases that alter neurotransmitter release from other neurons. Moreover, previous studies have shown that RGC spikes of shorter duration can fire at higher maximum frequencies. These properties should facilitate signal transfer by different mechanisms at RGC synapses onto subcortical target neurons.

L1CAM Is a Marker for Enriching Corticospinal Motor Neurons in the Developing Brain

The cerebral cortical tissue of murine embryo and pluripotent stem cell-derived neurons can survive in the adult brain and extend axons to the spinal cord. These features suggest that cell transplantation can be a strategy to reconstruct the corticospinal tract (CST). It is unknown, however, which cell population makes for safe and effective donor cells. To address this issue, we grafted the cerebral cortex of E14.5 mouse to the brain of adult mice and found that the cells in the graft extending axons along the CST expressed CTIP2. By using CTIP2:GFP knock-in mouse embryonic stem cells (mESCs), we identified L1CAM as a cell surface marker to enrich CTIP2+ cells. We sorted L1CAM+ cells from E14.5 mouse brain and confirmed that they extended a larger number of axons along the CST compared to L1CAM− cells. Our results suggest that sorting L1CAM+ cells from the embryonic cerebral cortex enriches subcortical projection neurons to reconstruct the CST.

Ultrastructural evidence for glutamatergic dysregulation in schizophrenia

The aim of this paper is to summarize ultrastructural evidence for glutamatergic dysregulation in several linked regions in postmortem schizophrenia brain. Following a brief summary of glutamate circuitry and how synapses are identified at the electron microscopic (EM) level, we will review EM pathology in the cortex and basal ganglia. We will include the effects of antipsychotic drugs and the relation of treatment response. We will discuss how these findings support or confirm other postmortem findings as well as imaging results. Briefly, synaptic and mitochondrial density in anterior cingulate cortex was decreased in schizophrenia, versus normal controls (NCs), in a selective layer specific pattern. In dorsal striatum, increases in excitatory synaptic density were detected in caudate matrix, a compartment associated with cognitive and motor function, and in the putamen patches, a region associated with limbic function and in the core of the nucleus accumbens. Patients who were treatment resistant or untreated had significantly elevated numbers of excitatory synapses in limbic striatal areas in comparison to NCs and responders. Protein levels of vGLUT2, found in subcortical glutamatergic neurons, were increased in the nucleus accumbens in schizophrenia. At the EM level, schizophrenia subjects had an increase in density of excitatory synapses in several areas of the basal ganglia. In the substantia nigra, the protein levels of vGLUT2 were elevated in untreated patients compared to NCs. The density of inhibitory synapses was decreased in schizophrenia versus NCs. In schizophrenia, glutamatergic synapses are differentially affected depending on the brain region, treatment status, and treatment response.

The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (Ritalin). Concomitant behavioral and neuronal recording study

Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals’ behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

MORTALITY FOR ALZHEIMER’S DISEASE IN BRAZIL FROM 2010 TO 2017

Introduction. The world population is aging and according to the World Health Organization (WHO), worldwide, the proportion of people aged 60 and over is growing rapidly, however, as life expectancy increases, neurodegenerative diseases and dementia may appear, such as Alzheimer’s Disease (AD), a progressive and fatal disorder resulting from the death of hippocampal and cholinergic neurons that are responsible for the functions of memory, learning, emotional control, reasoning and behavior. These changes are characterized by loss of subcortical and cortical neurons, and marked atrophy of the local cerebral cortex where nerve cells in the brain control memory, reasoning, and judgment. Moreover, it is believed that this pathology has a multifactorial etiology, which can be determined by risk factors such as gender, age, environmental and genetic factors, low educational level and inflammatory reactions. Goal. To verify the prevalence of deaths in Brazil from Alzheimer’s Disease in the period from 2010 to 2017. Method. A cross-sectional study was carried out by surveying the numbers of cases of death caused by Alzheimer’s disease in the regions of Brazil from 2010 to 2017, available in the DATASUS / TABNET database, using the following variables for the research: region, gender, age group and ethnicity. Results. During the period from 2010 to 2017, a total of 121,232 numbers of cases of deaths from Alzheimer’s Disease were recorded throughout Brazil. The Southeast region had a higher prevalence with 55.85% in relation to the number of deaths in the other regions. It was observed that the female gender was predominant in relation to the male gender with 64.58% of cases, while in the age group 74.31% had its prevalence at the age of 80 years or older, and finally in the ethnicity, there was a predominance. 74.36% in white people. Conclusion. The increase in life expectancy, is one of the risk factors for the development and death due to AD, especially in the age above 80 years, so it is of fundamental importance the creation of public policies that point and allow a real increase regarding to the care provided to the elderly, because even being a disease that has no cure, the diagnosis in its early stage for the delay of the process and symptoms is paramount, besides offering greater support, well-being and quality of life for these patients and relatives, enjoying a long life with respect and dignity.

The sour side of vitamin C might mediate neuroprotective, anticonvulsive and antidepressant-like effects

In animal experiments, neuroprotective, anticonvulsive and antidepressant-like properties have been increasingly attributed to administrations of ascorbic acid (AA, vitamin C) in at least medium (low millimolar) doses, which however await validation in well controlled clinical studies. In mammalian cortical and subcortical neurons, small to modest acidification (<0.4–0.5 pH-units) is belonging to the key strategies for controlling local excitability and is associated with neuroprotection, e.g. by limiting excitotoxicity. Such acidifications are furthermore involved in the mechanisms of some anticonvulsants and antidepressants. As AA-transport and regulation of intracellular pH (pHi) are closely interwoven on the level of special transmembrane solute carriers, I suppose that the aforementioned beneficial AA-effects might be based upon a discrete “hormetic” acidification of cortical and or subcortical neurons via an AA-mediated weakening of their pHi-regulation. This assumption is supported by findings in non-neuronal cells suggesting both, intracellular acidification and inhibition of a core-element of the pHi-regulation apparatus by millimolar AA. In mammalian subcortical neurons, there is already first evidence of a modest acidification after adding low millimolar AA.

Differential potentials of neural progenitors for the generation of neurons and non-neuronal cells in the developing amniote brain

Mature mammalian brains consist of variety of neuronal and non-neuronal cell types, which are progressively generated from embryonic neural progenitors through the embryonic and postnatal periods. However, it remains unknown whether all embryonic progenitors equivalently contribute to multiple cell types, or individual neural progenitors have variable potentials to generate specific cell types in a stochastic manner. Here, we performed population-level tracing of mouse embryonic neural progenitors by using Tol2-mediated genome integration vectors. We identified that neural progenitors in early embryonic stages predominantly contribute to cortical or subcortical neurons than astrocytes, ependymal cells, and neuroblasts in the postnatal brain. Notably, neurons and astrocytes were cumulatively labeled by the increase of total labeled cells, suggesting constant neurogenic and gliogenic potentials of individual neural progenitors. On the contrary, numbers of labeled ependymal cell are more fluctuated, implicating intrinsic variability of progenitor potentials for ependymal cell generation. Differential progenitor potentials that contribute to neurons, astrocytes, and ependymal cells were also detected in the developing avian pallium. Our data suggest evolutionary conservations of coherent and variable potentials of neural progenitors that generate multiple cell types in the developing amniote brain.

Parallel pathways for sound processing and functional connectivity among layer 5 and 6 auditory corticofugal neurons.

Cortical layers (L) 5 and 6 are populated by intermingled cell-types with distinct inputs and downstream targets. Here, we made optogenetically guided recordings from L5 corticofugal (CF) and L6 corticothalamic (CT) neurons in the auditory cortex of awake mice to discern differences in sensory processing and underlying patterns of functional connectivity. Whereas L5 CF neurons showed broad stimulus selectivity with sluggish response latencies and extended temporal non-linearities, L6 CTs exhibited sparse selectivity and rapid temporal processing. L5 CF spikes lagged behind neighboring units and imposed weak feedforward excitation within the local column. By contrast, L6 CT spikes drove robust and sustained activity, particularly in local fast-spiking interneurons. Our findings underscore a duality among sub-cortical projection neurons, where L5 CF units are canonical broadcast neurons that integrate sensory inputs for transmission to distributed downstream targets, while L6 CT neurons are positioned to regulate thalamocortical response gain and selectivity.

Hypoxia of Rats Subjected to Carotid Artery Ligation Results in Impaired Neurogenesis and Reduced Number of Cortical Neurons

Cerebral ischemia is a major cause of abnormal brain development. In a cerebral ischemia model, periventricular leukomalacia (PVL), white matter lesion and a decrease in the number of subcortical neurons were observed. The aim of this study was to investigate the effect of hypoxia on neurogenesis and cell survival. In seven-day postnatal rats, the right carotid artery was ligated. The rats were incubated either in a regular normoxic chamber (control group) or in a hypoxic chamber (PVL group, 8% 02 and 92% N2 at 37°C) for 2 h. Nestin- and NeuN-positive neurons were detected by immunohistochemistry. The densities of nestin-immunoreactivity (IR) cells in the cerebral parietal cortex and subventricular zone were increased with hypoxia. NeuN-IR cells in the cerebral cortex were significantly decreased in the PVL group. Perinatal white matter injury induced neurogenesis, while the survival of neurons was decreased in the cerebral cortex.

The onset and post-onset auditory responses of cochlear nucleus neurons are modulated differently by cortical activation

Auditory cortex exhibit a capacity of modulating the functions of subcortical auditory nuclei and even inner ear through descending pathways. The cochlear nucleus (CN), which acts as the gateway from the auditory periphery to the central auditory system, is also subjected to corticofugal modulation. Cortical modulation of subcortical nuclei is highly specific to the frequency tunings of cortical and subcortical neurons. It is unclear whether the high frequency-specificity of the cortical modulation of CN frequency tuning is implemented in the CN, in the auditory periphery, or in both. We analyzed the corticofugal effects on the frequency tuning, constructed from both onset (OS) and post-onset (pOS) response components of CN neurons in C57 mice. We found that the focal electrical stimulation of the primary auditory cortex (ESAI) induced remarkable changes in the response magnitude, response latency and the frequency response curves of CN neurons. The changes in the pOS components were highly specific to the difference in BFs between the stimulated AI neurons and recorded CN neurons. The changes in the OS component mostly involved the augmentation of the auditory responses of CN neurons, while exhibiting far poorer frequency-specificity. Considering the large differences in the temporal response patterns and the tuning shapes between the auditory nerve (AN) and the CN, our data suggest that the CN intrinsic neural circuitry plays a critical role in the frequency specificity of corticofugal modulation. Cortical modulation of the inner ear mostly contributes to the augmentation of the AN inputs to the CN, around the BFs of stimulated AI neurons.

Serine residues in the α4 nicotinic acetylcholine receptor subunit regulate surface α4β2* receptor expression and clustering

Background and purposeChronic nicotine exposure upregulates α4β2* nicotinic acetylcholine receptors (nAChRs) in the brain. The goal of this study was to examine the role of three serine residues in the large cytoplasmic loop of the α4 subunit on α4β2* upregulation in neurons. Experimental approachSerine residues S336, S470 and S530 in mouse α4 were mutated to alanine and then re-expressed in primary neurons from cortex, hippocampus and subcortex of α4 KO mice. Mutant and wild type α4 expressing neurons were treated with nicotine (0.1, 1 and 10 μM) and assessed for α4β2* upregulation. Key resultsα4β2* nAChRs expressing S336A or S470A mutants were deficient at cell surface upregulation in both subcortex and hippocampal neurons. S530A α4β2* mutants exhibited aberrant surface upregulation in subcortical neurons. None of the mutants affected surface upregulation in cortical neurons or upregulation of total α4β2* binding sites in any region. Further, dense domains or clusters of α4β2* nAChRs were observed in the neuronal surface. The impact of nicotine exposure on the intensity, area, and density of these clusters was dependent upon individual mutations. Conclusions and implicationsEffects of α4 nAChR mutants on surface upregulation varied among brain regions, suggesting that the cellular mechanism of α4β2* upregulation is complex and involves cellular identity. We also report for the first time that α4β2* nAChRs form clusters on the neuronal surface and that nicotine treatment alters the characteristics of the clusters in an α4 mutant-dependent manner. This finding adds a previously unknown layer of complexity to the effects of nicotine on α4β2* expression and function.

Pattern-sensitive neurons reveal encoding of complex auditory regularities in the rat inferior colliculus

A ‘pattern alternation paradigm’ has been previously used in human ERP recordings to investigate the brain encoding of complex auditory regularities, but prior studies on regularity encoding in animal models to examine mechanisms of adaptation of auditory neuronal responses have used primarily oddball stimulus sequences to study stimulus-specific adaptation alone. In order to examine the sensitivity of neuronal adaptation to expected and unexpected events embedded in a complex sound sequence, we used a similar patterned sequence of sounds. We recorded single unit activity and compared neuronal responses in the rat inferior colliculus (IC) to sound stimuli conforming to pattern alternation regularity with those to stimuli in which occasional sound repetitions violated that alternation.Results show that some neurons in the rat inferior colliculus are sensitive to the history of patterned stimulation and to violations of patterned regularity, demonstrating that there is a population of subcortical neurons, located as early as the level of the midbrain, that can detect more complex stimulus regularities than previously supposed and that are as sensitive to complex statistics as some neurons in primary auditory cortex.Our findings indicate that these pattern-sensitive neurons can extract temporal and spectral regularities between successive acoustic stimuli. This is important because the extraction of regularities from the sound sequences will result in the development of expectancies for future sounds and hence, the present results are compatible with predictive coding models. Our results demonstrate that some collicular neurons, located as early as in the midbrain level, are involved in the generation and shaping of prediction errors in ways not previously considered and thus, the present findings challenge the prevailing view that perceptual organization of sound only emerges at the auditory cortex level.

Recent advances in understanding the auditory cortex.

Our ability to make sense of the auditory world results from neural processing that begins in the ear, goes through multiple subcortical areas, and continues in the cortex. The specific contribution of the auditory cortex to this chain of processing is far from understood. Although many of the properties of neurons in the auditory cortex resemble those of subcortical neurons, they show somewhat more complex selectivity for sound features, which is likely to be important for the analysis of natural sounds, such as speech, in real-life listening conditions. Furthermore, recent work has shown that auditory cortical processing is highly context-dependent, integrates auditory inputs with other sensory and motor signals, depends on experience, and is shaped by cognitive demands, such as attention. Thus, in addition to being the locus for more complex sound selectivity, the auditory cortex is increasingly understood to be an integral part of the network of brain regions responsible for prediction, auditory perceptual decision-making, and learning. In this review, we focus on three key areas that are contributing to this understanding: the sound features that are preferentially represented by cortical neurons, the spatial organization of those preferences, and the cognitive roles of the auditory cortex.

Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum.

Rhythmic theta frequency (~5-12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of 'upstream' and 'downstream' cortico-cortical circuits involved in mnemonic functions.

Interneuron synaptopathy in developing rat cortex induced by the pro-inflammatory cytokine LIF

Pro-inflammatory cytokines of the IL-6 family have been linked to the etiology of epilepsy and mental disorders. After infusion of the IL-6 family member leukemia inhibitory factor (LIF) into postnatal day 12–20 rat visual cortex (period of synaptogenesis; equals early childhood in human) and equivalent ages in organotypic cultures (OTC), somatic growth of cortical and subcortical neurons is delayed, expression of interneuron markers reduced and expression of neurotrophins transiently reduced. Further, LIF prevents NT4 from promoting soma growth of GABA-ergic interneurons. We now show that LIF-treatment from DIV 12–20 in OTC compromises the differentiation of fast-spiking GABA-ergic basket neurons: GAD-65/67, Kv3.2, and synaptotagmin-2 proteins are reduced, dendrites are shorter, and axonal varicosities are smaller. Bitufted and Martinotti interneurons are barely affected. Pyramidal cells display lower dendritic spine densities, more filopodia, and shorter axon initial segments. βIV-spectrin, Cav3.1, GABAA receptor subunits α1 and α2, and the phosphorylation of GluN2B at Y1472 are reduced. The frequency of calcium events in pyramidal cells and interneurons is increased, and the antiepileptic neuropeptide Y is upregulated, suggesting a hyperexcitability of the network. In the presence of LIF, neurotrophins fail to activate MAP kinase phosphorylation and c-fos expression, and exogenous NT4 fails to promote the maturation of pyramidal cells and interneurons as it normally would. After discontinuing LIF treatment, bouton size and expression levels of affected proteins normalize except for synaptotagmin-2; moreover, hyperexcitability persists. The results suggest that elevated levels of inflammatory cytokines during this developmental period cause a lasting maldevelopment in particular of basket cells.

Dynamic modulation of activity in cerebellar nuclei neurons during pavlovian eyeblink conditioning in mice.

While research on the cerebellar cortex is crystallizing our understanding of its function in learning behavior, many questions surrounding its downstream targets remain. Here, we evaluate the dynamics of cerebellar interpositus nucleus (IpN) neurons over the course of Pavlovian eyeblink conditioning. A diverse range of learning-induced neuronal responses was observed, including increases and decreases in activity during the generation of conditioned blinks. Trial-by-trial correlational analysis and optogenetic manipulation demonstrate that facilitation in the IpN drives the eyelid movements. Adaptive facilitatory responses are often preceded by acquired transient inhibition of IpN activity that, based on latency and effect, appear to be driven by complex spikes in cerebellar cortical Purkinje cells. Likewise, during reflexive blinks to periocular stimulation, IpN cells show excitation-suppression patterns that suggest a contribution of climbing fibers and their collaterals. These findings highlight the integrative properties of subcortical neurons at the cerebellar output stage mediating conditioned behavior.