Short-term synaptic enhancement and long-term potentiation in neocortex.

Repetitive stimuli reliably induce long-term potentiation (LTP) of synapses in the upper layers of the granular somatosensory cortex but not the agranular motor cortex of rats. Herein we examine, in these same cortical areas, short-term changes in synaptic strength that occur during the LTP induction period. theta-Burst stimulation produced a strong short-term enhancement of synapses in the granular area but only weak enhancement in the agranular area. The magnitude of enhancement during stimulation was strongly correlated with the magnitude of LTP subsequently expressed. Short-term enhancement was abolished by an antagonist of N-methyl-D-aspartate (NMDA) receptors but remained in the presence of a non-NMDA receptor antagonist. Inhibitory postsynaptic potentials of the granular and agranular areas displayed similar frequency sensitivity, but the frequency sensitivity of NMDA receptor-dependent excitatory postsynaptic potentials differed significantly between areas. We propose that pathway-specific differences in short-term enhancement are due to variations in the frequency dependence of NMDA currents; different capacities for short-term enhancement may explain why repetitive stimulation more readily induces LTP in the somatosensory cortex than in the motor cortex.     

Spontaneous and evoked coccygeal pain in depression

Three hundred thirteen patients with signs of depression or spontaneous or evoked pain of coccygeal area were studied over six months. One hundred eighty (58 percent) had no spontaneous pain, 87 (28 percent) had moderate pain, and 46 (15 percent) a severe coccygodynia leading to consultation. In four of the latter group, no other sign of depression was found. Seventy-nine percent of the patients with spontaneous pain and 66 percent without spontaneous pain had coccygeal pain evoked by rectal digital examination (RDE). Seventy-one percent of the patients with spontaneous pain and 56 percent without spontaneous pain had paracoccygeal pain evoked by RDE. Among severely depressed patients (Group III), 76 percent had an evoked pain and 80 percent a coccygeal pain--either spontaneous or evoked. In 178 (57 percent), all signs disappeared when treated with various antidepressants in seven visits and within six months. Seven (2 percent) were failures; 44 (14 percent) were lost during follow-up; 84 (27 percent) did not return after the first consultation. After treatment in five patients was stopped, all signs recurred together and disappeared when adapted treatment was administered again. In 120 consecutive patients who had colonic roentgenologic examination and no depressive sign, two had coccygeal and muscular pain at rectal touch. A highly significant correlation was found between the following parameters: evoked pain and depressive status in noncoccygodynic patients, coccygodynia and evoked pain, coccygeal and paracoccygeal muscular pain. Severity of coccygodynia was not correlated with the number of depressive signs. Sex, age, and treatment efficiency were not correlated. The mechanism of depressive pain is discussed. RDE-evoked pain is proposed as an "objective" diagnostic sign for masked depression and as a means of evolution control. The frequency of the disease and efficiency of treatment are stressed.     

Spontaneous activity competes with externally evoked responses in sensory cortex

The interaction between spontaneous and externally evoked neuronal activity is fundamental for a functional brain. Increasing evidence suggests that bursts of high-power oscillations in the 15- to 30-Hz beta-band represent activation of internally generated events and mask perception of external cues. Yet demonstration of the effect of beta-power modulation on perception in real time is missing, and little is known about the underlying mechanism. Here, we used a closed-loop stimulus-intensity adjustment system based on online burst-occupancy analyses in rats involved in a forepaw vibrotactile detection task. We found that the masking influence of burst occupancy on perception can be counterbalanced in real time by adjusting the vibration amplitude. Offline analysis of firing rates (FRs) and local field potentials across cortical layers and frequency bands confirmed that beta-power in the somatosensory cortex anticorrelated with sensory evoked responses. Mechanistically, bursts in all bands were accompanied by transient synchronization of cell assemblies, but only beta-bursts were followed by a reduction of FR. Our closed loop approach reveals that spontaneous beta-bursts reflect a dynamic state that competes with external stimuli.

The brain is constantly active, even at resting states in the absence of external stimuli (1). Spontaneously active resting-state networks (RSNs) were found in memory, visual, auditory, tactile, and sensorimotor regions, with activity patterns similar to task-evoked responses (2, 3). Functional connectivity studies in humans suggest that a default network, spontaneously activated at resting states and deactivated upon increased cognitive demands, antagonizes a network involved in active attention to external sensory input (4–8). However, whether the activity in different networks is anticorrelated is under debate, and their antagonizing mechanisms and influence on local circuits remain unknown (9).Here, we utilized the occupancy of high-power bursts in the beta-band (15 to 30 Hz) of local field potentials (LFPs) as an indicator of spontaneous activity to investigate its influence on detection in real time. Several lines of evidence relate the RSN to beta-bursts. First, spontaneous correlated oscillatory activity in beta (termed “beta-connectome”) (10) was reported in anatomical regions corresponding to the RSN (11, 12). A recent study derived this beta-connectome from burst occupancy (10). Second, beta-oscillations are dominant during the resting state (13) and bursts are responsible for virtually all beta-band power modulation (14). Third, task-dependent desynchronization of beta was observed in the somatosensory (15, 16), visual (17), auditory (18), and motor (19) cortices, resembling RSN deactivation (4, 7). The task-dependent averaged power modulation was attributed to changes in burst rates in rodents, nonhuman primates, and humans (14, 20, 21). Fourth, the burst duration (50 to a few hundred milliseconds) (22) is similar to “packets” of neural activity, which are conceived as messages initiated in a particular cortical region and spread as a wave over the cortex. Most of these packets are generated spontaneously, and spontaneous and sensory-evoked packets are remarkably similar (23).We found that bursts in all bands indicate transient synchronization of flexible neuronal networks, but only beta-bursts were followed by a reduction in population firing rate (FR). High occupancies of beta-bursts predicted reduced detection, and this effect can be counterbalanced bidirectionally in real time by adjusting the stimulus intensity according to burst occupancy.     

Spontaneous and evoked EEG-activity during one-second light-stimulation (author's transl)]

EEG data were recorded in 13 students during one-second light-stimulation with eyes closed and sometimes eyes opened, from central and occipital regions. The background EEG was computer-analyzed in the alpha-band using the power time course where a short decrease in power was indicative of a phasic desynchronization of the rhythmic activity within the alpha-band. The maximal desynchronization was observed in the occipital region independent of eyes-opened or eyes-closed conditions. With eyes closed a reinforced power decrease was found 0.25-0.5 sec after the on- and offset of light-stimulation, which was interpreted as "on"- and "off"- effect of the background EEG activity. Parallel with the on- and off-effect a slow potential change occurred in the evoked responses. The behaviour of the background activity during 1 sec light-stimulation was intramodality specific in contrast to the evoked response which showed an intramodality unspecific behaviour with maximal amplitude in the central region.     

Age-dependent decrease of synaptic plasticity in the neocortex of αCaMKII mutant mice

Synaptic long-term potentiation (LTP) and long-term depression (LTD) were studied in the visual cortex of mutant mice lacking α-calcium/calmodulin-dependent protein kinase II (αCaMKII). In adult mutants, little LTD or LTP could be elicited using standard conditioning protocols. However, substantial LTD and LTP were induced in 4- to 5-week-old mutants. Thus, the reduction in cortical plasticity in αCaMKII (−/−) mice is conditional, with the relevant condition being postnatal age.     

Spontaneous and evoked release of prothoracicotropin from multiple neurohemal organs of the tobacco hornworm

Release of neurohormone from putative cephalic neurohemal organs was directly demonstrated in an insect. The prothoracicotropic hormone (PTTH) of the tobacco hornworm, Manduca sexta, was measured indirectly by its ability to stimulate the secretion of α-ecdysone by inactive prothoracic glands; the ecdysone was measured by radioimmunoassay. The PTTH released spontaneously from intact brain-retrocerebral complexes was localized to the retrocerebral complex by placing a waxy barrier across the nerves connecting the corpora cardiaca to the brain. Isolated corpora allata spontaneously released much more PTTH than did either isolated corpora cardiaca or isolated brains. Media containing 100 mM potassium stimulated PTTH release from both isolated corpora allata and isolated corpora cardiaca. In calcium-free media, spontaneous PTTH release was diminished and release could not be stimulated by high potassium. These results indicate that depolarization of the neurosecretory cells is correlated with calcium-dependent neurohormone release and that there are multiple neurohemal organs for PTTH. The biological activities of stored and circulating PTTH are compared.     

Aging and the human neocortex

Neurostereology has been applied to quantitative anatomical study of the human brain. Such studies have included the total neocortical number of neurons and glial cells, the estimated size distribution of neocortical neurons, the total myelinated fiber length in the brain white matter, the total number of synapses in the neocortex, and the effect of normal aging on these structural elements. The difference in total number of neurons was found to be less than 10% over the age range from 20 to 90 years, while the glial cell number in six elderly individuals, mean age 89.2 years, showed an average number of 36 billion glial cells, which was not statistically significantly different from the 39 billion glial cells in the neocortex of six young individuals with a mean age of 26.2 years. The total myelinated fiber length varied from 150,000 to 180,000 km in young individuals and showed a large reduction as a function of age. The total number of synapses in the human neocortex is approximately 0.15 x 10(15) (0.15 quadrillion). Although the effect of aging is seen in all estimated structural elements, the effect of sex is actually higher. The functional relevance of these differences in neuron numbers in both age and gender is not known.     

Cooperative synapse formation in the neocortex

Neuron morphology plays an important role in defining synaptic connectivity. Clearly, only pairs of neurons with closely positioned axonal and dendritic branches can be synaptically coupled. For excitatory neurons in the cerebral cortex, such axo-dendritic oppositions, termed potential synapses, must be bridged by dendritic spines to form synaptic connections. To explore the rules by which synaptic connections are formed within the constraints imposed by neuron morphology, we compared the distributions of the numbers of actual and potential synapses between pre- and postsynaptic neurons forming different laminar projections in rat barrel cortex. Quantitative comparison explicitly ruled out the hypothesis that individual synapses between neurons are formed independently of each other. Instead, the data are consistent with a cooperative scheme of synapse formation where multiple-synaptic connections between neurons are stabilized while neurons that do not establish a critical number of synapses are not likely to remain synaptically coupled.     

Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus

Thyroid hormones are essential for neonatal brain development. It is well established that insufficiency of thyroid hormone during critical periods of development can impair cognitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well understood. As impairments in synaptic function are likely to contribute to cognitive deficits, the current study tested whether thyroid hormone insufficiency during development would alter quantitative characteristics of synaptic function in the hippocampus. Developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, administered in the drinking water of dams from gestation d 6 until postnatal day (PN) 30. Excitatory postsynaptic potentials and population spikes were recorded from the stratum radiatum and the pyramidal cell layer, respectively, in area CA1 of hippocampal slices from offspring between PN21 and PN30. Baseline synaptic transmission was evaluated by comparing input-output relationships between groups. Paired-pulse facilitation, paired-pulse depression, long-term potentiation, and long-term depression were recorded to examine short- and long-term synaptic plasticity. PTU reduced thyroid hormones, reduced body weight gain, and delayed eye-opening in a dose-dependent manner. Excitatory synaptic transmission was increased by developmental exposure to PTU. Thyroid hormone insufficiency was also dose-dependently associated with a reduction paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. The results indicate that thyroid hormone insufficiency compromises the functional integrity of synaptic communication in area CA1 of developing rat hippocampus and suggest that these changes may contribute to learning deficits associated with developmental hypothyroidism.     

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo. We demonstrate that the organ of Corti has the intrinsic capacity to replenish IBCs/IPhCs effectively during early postnatal development. Repopulation depends on the presence of hair cells and cells within the greater epithelial ridge and is independent of cell proliferation. This plastic response in the neonatal cochlea preserves neuronal survival, afferent innervation, and hearing sensitivity in adult mice. In contrast, the capacity for IBC/IPhC regeneration is lost in the mature organ of Corti, and consequently IHC survival and hearing sensitivity are impaired significantly, demonstrating that there is a critical period for the regeneration of cochlear supporting cells. Our findings indicate that the quiescent neonatal organ of Corti can replenish specific supporting cells completely after loss in vivo to guarantee mature hearing function.Inner hair cells (IHCs), the sensory cells of the mammalian auditory sensory epithelium, are surrounded by specialized supporting cells (SCs) called “inner border cells” (IBCs) and “inner phalangeal cells” (IPhCs) (Fig. S1A). IBCs and IPhCs, together with other SCs, are known to play critical roles during the development and maturation of the organ of Corti, in processes such as patterning of the epithelium, synaptogenesis, and initiation of electrical activity in auditory nerves before the onset of hearing and formation of extracellular matrices (1–7). SCs also are essential for the function of the mature organ of Corti, where they contribute to the maintenance of the reticular lamina at the apical surface of the epithelium (8), control the extracellular concentration of ions (e.g., K⁺) (9, 10) and neurotransmitters (e.g., glutamate) (11), and support hair cell (HC) and auditory sensory neuron survival (5, 12–15). SCs also have been proposed to regulate the effects of insults on HCs by releasing molecules that either promote (e.g., ERK1 and 2) (16) or reduce (e.g., heat shock protein 70) (17) HC death. Additionally, SCs impact the extent of damage in the auditory epithelium through scar formation and clearance of HC debris (18). Furthermore, SCs are considered a potential source of cells for HC replacement in mammals, because SCs are a documented source of new HCs in cultured neonatal cochlea (19) and in adult utricles (20). Additionally, nonmammalian vertebrates regenerate HCs and SCs after damage and recover hearing, with the SCs being the source of the regenerative response (21–23). Indeed, if SCs are damaged by insults, the regenerative response is severely compromised (1, 24). Thus, it is assumed that the presence of these cells in the postnatal cochlea is essential for hearing, but specific roles of IBCs and IPhCs in HC maintenance and cochlear function have not been established.To determine the consequences of neonatal IBC and IPhC loss on the mature organ of Corti, we ablated these cells in vivo using an inducible diphtheria toxin fragment A (DTA) transgenic approach (25). Unexpectedly, we found that when these IHC supporting cells are eliminated immediately after birth, they are replaced efficiently within days. Moreover, this regeneration preserves the structure and function of the organ of Corti, so that mice with transient IBC/IPhC loss retain normal hearing as adults. In contrast, IBCs and IPhCs do not regenerate if ablation occurs after the onset of hearing, resulting in IHC loss and severe hearing impairment. Our studies also indicate that IBC and IPhC replacement in the neonatal cochlea results from transdifferentiation of less-specified SCs within the neighboring greater epithelial ridge (GER or Kölliker’s organ), which does not require cell proliferation. The unexpected regenerative capacity of SCs in the early postnatal organ of Corti in vivo may provide new strategies to regenerate its nonsensory and sensory cells after damage.     

脑干听觉诱发电位诊断新生儿高胆红素血症的临床应用价值

目的 探讨应用脑干听觉诱发电位(BAEP)诊断新生儿高胆红素血症的临床价值.方法 选择2017-08～2019-08阳春市妇幼保健院收治的98例高胆红素血症新生儿作为观察组,另选择同期98名健康新生儿作为对照组.两组均施行BAEP检测,并比较检测结果.结果 观察组有71例(72.45％)发生BAEP异常,对照组有6例(...     

Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming

Synaptic vesicles must be primed to fusion competence before they can fuse with the plasma membrane in response to increased intracellular Ca2+ levels. The presynaptic active zone protein Munc13-1 is essential for priming of glutamatergic synaptic vesicles in hippocampal neurons. However, a small subpopulation of synapses in any given glutamatergic nerve cell as well as all gamma-aminobutyratergic (GABAergic) synapses are largely independent of Munc13-1. We show here that Munc13-2, the only Munc13 isoform coexpressed with Munc13-1 in hippocampus, is responsible for vesicle priming in Munc13-1 independent hippocampal synapses. Neurons lacking both Munc13-1 and Munc13-2 show neither evoked nor spontaneous release events, yet form normal numbers of synapses with typical ultrastructural features. Thus, the two Munc13 isoforms are completely redundant in GABAergic cells whereas glutamatergic neurons form two types of synapses, one of which is solely Munc13-1 dependent and lacks Munc13-2 whereas the other type employs Munc13-2 as priming factor. We conclude that Munc13-mediated vesicle priming is not a transmitter specific phenomenon but rather a general and essential feature of multiple fast neurotransmitter systems, and that synaptogenesis during development is not dependent on synaptic secretory activity.     

Modified climbing fiber/Purkinje cell synaptic connectivity in the cerebellum of the neonatal phencyclidine model of schizophrenia

Environmental perturbations during the first years of life are a major factor in psychiatric diseases. Phencyclidine (PCP), a drug of abuse, has psychomimetic effects, and neonatal subchronic administration of PCP in rodents leads to long-term behavioral changes relevant for schizophrenia. The cerebellum is increasingly recognized for its role in diverse cognitive functions. However, little is known about potential cerebellar changes in models of schizophrenia. Here, we analyzed the characteristics of the cerebellum in the neonatal subchronic PCP model. We found that, while the global cerebellar cytoarchitecture and Purkinje cell spontaneous spiking properties are unchanged, climbing fiber/Purkinje cell synaptic connectivity is increased in juvenile mice. Neonatal subchronic administration of PCP is accompanied by increased cFos expression, a marker of neuronal activity, and transient modification of the neuronal surfaceome in the cerebellum. The largest change observed is the overexpression of Ctgf, a gene previously suggested as a biomarker for schizophrenia. This neonatal increase in Ctgf can be reproduced by increasing neuronal activity in the cerebellum during the second postnatal week using chemogenetics. However, it does not lead to increased climbing fiber/Purkinje cell connectivity in juvenile mice, showing the complexity of PCP action. Overall, our study shows that administration of the drug of abuse PCP during the developmental period of intense cerebellar synaptogenesis and circuit remodeling has long-term and specific effects on Purkinje cell connectivity and warrants the search for this type of synaptic changes in psychiatric diseases.

Phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist initially developed for its properties as an anesthetic, became a popular drug of abuse in the 1960s (1, 2). Nowadays, PCP is often mixed with other drugs, in particular marijuana, and a US 2013 report estimated that PCP-related emergency department visits increased more than 400% between 2005 and 2011 (https://www.samhsa.gov/data/sites/default/files/DAWN143/DAWN143/sr143-emergency-phencyclidine-2013.htm). PCP has important psychotomimetic effects, such as alterations of body image, feelings of estrangement and loneliness, and disorganization of thought. Repeated use of PCP induces persistent symptoms found in schizophrenia, including both positive (hallucinations, psychosis…), cognitive and negative (social withdrawal) effects. PCP also produces regressive symptoms in schizophrenic patients. These observations led to the NMDA hypothesis of schizophrenia and the development of animal models using both acute and chronic PCP administration to study the pathophysiology of this disease (3). Because schizophrenia is now considered a developmental disorder, neonatal administration of PCP in rodents has been tested and shown to produce a wide range of behavioral alterations in the adult, including spatial memory deficits (4, 5) and a deficit in social novelty discrimination (6–8). Some studies found defects in prepulse inhibition (PPI) of the startle response, a sensorimotor gating task used both in animal models and in humans as a behavioral marker of psychiatric disorders (4, 9, 10). Interestingly, these PPI deficits last even after withdrawal, which is not the case when PCP is administered in adulthood, suggesting that this aspect of the disease is better modeled by neonatal administration of PCP. Finally, PCP abuse during pregnancy has been associated with neurobehavioral defects (11) and with long-term consequences on social behavior and motor control in children (12), further highlighting the need to understand the consequences of PCP exposure on the development of neuronal networks.In the subchronic neonatal PCP model, the drug is administered three times during the second postnatal week in rodents (Fig. 1A), a period of intense neuronal growth and synaptogenesis. This developmental stage is particularly sensitive to early environmental stressors associated with increased risk of developing schizophrenia in humans (13). Histopathological and genetic studies have revealed that schizophrenia is a synaptopathy. Mutations and expression changes have been found in genes coding for synaptic proteins (14–19) (a meta-analysis is in ref. 20). Postmortem studies of the cortex of patients with schizophrenia have revealed deficits in dendritic arborization, spine densities, and the number of parvalbumin interneurons (21–25). Similar spine and cellular deficits have been reported in the PCP neonatal model (5, 26, 27), as well as impaired function of both excitatory and inhibitory synapses (28–30). It is, however, still unclear whether these common alterations in schizophrenia and the neonatal PCP model are due to the direct inhibition of NMDA function or a complex interaction between perturbations of neuronal activity and genetic factors.Open in a separate windowFig. 1.Neonatal PCP administration does not modify the cytoarchitecture of the cerebellum and the spontaneous activity of PCs. (A) Experimental design. PCP (10 mg/kg) or vehicle is injected subcutaneously in mouse pups at P7, P9, and P11. Morphological and electrophysiological analyses are performed at P30. (B) Parasagittal cerebellar sections from the vermis of P30 mice were immunolabeled with an anti-calbindin antibody to stain PCs in their entirety and reveal cerebellar cytoarchitecture. Quantification of the mean area of cerebellar slices showed no significant differences between the two conditions (mean ± SEM; vehicle: n = 12 animals; PCP: n = 12; P = 0.0962, Student’s t test). Representative images from PCs and their dendritic tree in lobule VI reveal similar morphology in sections from P30 vehicle- and PCP-treated animals. Quantification of the thickness of the molecular layer (ML) in the lobule VI, measured as the length from the beginning of the primary dendrite of PCs in the Purkinje cell layer (PCL) to the upper extremity of the ML, reveals no significant difference between vehicle- and PCP-treated animals (lobule VI is shown here; mean ± SEM; vehicle: n = 14 animals; PCP: n = 16 animals; P = 0.964, unpaired Student’s t test). (Scale bars: Upper, 1,000 µm; Lower, 50 µm.) (C) High-density MEAs were used to record PC spontaneous spiking in acute cerebellar slices from P30 mice. An example of the recorded electrical activity in a cerebellar slice from a vehicle-treated mouse is shown with each pixel representing one channel and units showing high activity in red and low activity in blue. A representative trace of recordings from one channel is shown for each condition. Spike sorting using the SpyKING CIRCUS software allowed for estimation of the mean firing rate and mean interspike interval (ISI) CV and CV2. No significant difference was detected in any of these parameters (mean ± SEM; vehicle: n = 7 animals; PCP, n = 9 animals; unpaired Student’s t test).While initially thought to be a motor-related structure, it is now well established that the cerebellum also plays a role in cognitive processes (31, 32), such as spatial navigation (33), language (34), reward (35), and social cognition (36). In addition, while schizophrenia has been primarily thought of as a disease of the prefrontal cortex or hippocampus, the cerebellum has emerged as a potential actor in this pathology. Schizophrenic patients often present a decreased cerebellar volume (37–39) as well as neurological soft signs, a type of sensorimotor impairment that implicates the cerebellum (40). Interestingly, neurological soft signs have been correlated with a poor outcome and greater negative and cognitive symptoms (41–43). A significant correlation between negative symptoms in schizophrenia and diminished connectivity between the dorsolateral prefrontal cortex and vermal posterior cerebellum was found in a study of whole-brain connectivity using resting-state functional magnetic resonance imaging in schizophrenic patients (44). It is, however, still unknown whether synaptic deficits are present in the cerebellum of schizophrenic patients.NMDA receptors are present in many neurons of the olivocerebellar circuit, such as molecular layer interneurons (45), granule cells (GCs) (46, 47), inferior olivary neurons (IONs) (48), and Purkinje cells (PCs) themselves (49). In the cerebellum, NMDA receptors participate in the control of neuronal survival (50), circuit maturation, and function (51–53), suggesting that neonatal administration of PCP, an NMDA antagonist, could directly impact the development of the olivocerebellar circuit. In this study, we combined morphological, electrophysiological, and molecular approaches to study the olivocerebellar network in the PCP neonatal model. Lasting synaptic changes were detected in juvenile mice, in particular at the climbing fiber (CF)/PC excitatory synapses, which are key for cerebellar computation. PCP was also found to induce a transient misregulation of the expression pattern of genes coding for membrane and secreted proteins in the cerebellum. The largest misregulation was found for connective tissue growth factor (Ctgf), a gene previously documented as a biomarker in schizophrenic patients. Reproducing the transient misregulation of Ctgf during the second postnatal week using chemogenetics was not sufficient to recapitulate the long-term synaptic changes induced by PCP in the olivocerebellar network. Altogether, neonatal subchronic administration of PCP leads to acute changes in gene expression and long-term synaptic connectivity modifications in the olivocerebellar circuit.     

Cell-type homologies and the origins of the neocortex

The six-layered neocortex is a uniquely mammalian structure with evolutionary origins that remain in dispute. One long-standing hypothesis, based on similarities in neuronal connectivity, proposes that homologs of the layer 4 input and layer 5 output neurons of neocortex are present in the avian forebrain, where they contribute to specific nuclei rather than to layers. We devised a molecular test of this hypothesis based on layer-specific gene expression that is shared across rodent and carnivore neocortex. Our findings establish that the layer 4 input and the layer 5 output cell types are conserved across the amniotes, but are organized into very different architectures, forming nuclei in birds, cortical areas in reptiles, and cortical layers in mammals.     

Inosine induces axonal rewiring and improves behavioral outcome after stroke

Cerebral infarct (stroke) often causes devastating and irreversible losses of function, in part because of the brain's limited capacity for anatomical reorganization. The purine nucleoside inosine has previously been shown to induce neurons to express a set of growth-associated proteins and to extend axons in culture and in vivo. We show here that in adult rats with unilateral cortical infarcts, inosine stimulated neurons on the undamaged side of the brain to extend new projections to denervated areas of the midbrain and spinal cord. This growth was paralleled by improved performance on several behavioral measures.