The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury

A reorganization of cortical representations is postulated as the basis for functional recovery following many types of nervous system injury. Neuronal mechanisms underlying this form of cortical plasticity are poorly understood. The present study investigated the hypothesis that the basal forebrain cholinergic system plays an essential role in enabling the cortical reorganization required for functional recovery following brain injury. The results demonstrate that functional recovery following cortical injury requires basal forebrain cholinergic mechanisms and suggest that the basis for this recovery is the cholinergic-dependent reorganization of motor representations. These findings raise the intriguing possibility that deficits in cholinergic function may limit functional outcomes following nervous system injury.     

Cholinergic modulation of skill learning and plasticity

The basal forebrain cholinergic system strongly influences both cortical plasticity and learning. Directly relating these two roles has proven difficult. New results indicate that nucleus basalis lesions prevent motor cortex map plasticity and impair skill learning. These results strengthen the hypothesis that nucleus basalis gates neural plasticity necessary for instrumental learning.     

Basal forebrain cholinergic input is not essential for lesion-induced plasticity in mature auditory cortex

The putative role of the basal forebrain cholinergic system in mediating lesion-induced plasticity in topographic cortical representations was investigated. Cholinergic immunolesions were combined with unilateral restricted cochlear lesions in adult cats, demonstrating the consequence of cholinergic depletion on lesion-induced plasticity in primary auditory cortex (AI). Immunolesions almost eliminated the cholinergic input to AI, while cochlear lesions produced broad high-frequency hearing losses. The results demonstrate that the near elimination of cholinergic input does not disrupt reorganization of the tonotopic representation of the lesioned (contralateral) cochlea in AI and does not affect the normal representation of the unlesioned (ipsilateral) cochlea. It is concluded that cholinergic basal forebrain input to AI is not essential for the occurrence of lesion-induced plasticity in AI.     

Cortical map plasticity improves learning but is not necessary for improved performance

Cortical map plasticity is believed to be a key substrate of perceptual and skill learning. In the current study, we quantified changes in perceptual ability after pairing tones with stimulation of the cholinergic nucleus basalis to induce auditory cortex map plasticity outside of a behavioral context. Our results provide evidence that cortical map plasticity can enhance perceptual learning. However, auditory cortex map plasticity fades over weeks even though tone discrimination performance remains stable. This observation is consistent with recent reports that cortical map expansions associated with perceptual and motor learning are followed by a period of map renormalization without a decrement in performance. Our results indicate that cortical map plasticity enhances perceptual learning, but is not necessary to maintain improved discriminative ability.     

Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cord.

The motor cortex and spinal cord possess the remarkable ability to alter structure and function in response to differential motor training. Here we review the evidence that the corticospinal system is not only plastic but that the nature and locus of this plasticity is dictated by the specifics of the motor experience. Skill training induces synaptogenesis, synaptic potentiation, and reorganization of movement representations within motor cortex. Endurance training induces angiogenesis in motor cortex, but it does not alter motor map organization or synapse number. Strength training alters spinal motoneuron excitability and induces synaptogenesis within spinal cord, but it does not alter motor map organization. All three training experiences induce changes in spinal reflexes that are dependent on the specific behavioral demands of the task. These results demonstrate that the acquisition of skilled movement induces a reorganization of neural circuitry within motor cortex that supports the production and refinement of skilled movement sequences. We present data that suggest increases in strength may be mediated by an increased capacity for activation and/or recruitment of spinal motoneurons while the increased metabolic demands associated with endurance training induce cortical angiogenesis. Together these results show the robust pattern of anatomic and physiological plasticity that occurs within the corticospinal system in response to differential motor experience. The consequences of such distributed, experience-specific plasticity for the encoding of motor experience by the motor system are discussed.     

鸣禽前脑X区结构功能的研究进展

鸣禽鸣唱与人类说话一样,都是在教习和听觉反馈下形成的感知运动学习过程。鸣禽鸣唱的发育和成熟巩固依赖于发声通路和前端脑通路组成的鸣唱系统的完整。前端脑通路中的X区在鸣唱学习记忆中扮演着重要角色。本文就X区的形态组织结构、在鸣唱发育与成熟巩固中的作用、突触可塑性的研究进展进行了综述,并且将X区与哺乳动物基底神经节的学习记忆功能做了比较。     

A neural field model of the somatosensory cortex: formation, maintenance and reorganization of ordered topographic maps

We investigate the formation and maintenance of ordered topographic maps in the primary somatosensory cortex as well as the reorganization of representations after sensory deprivation or cortical lesion. We consider both the critical period (postnatal) where representations are shaped and the post-critical period where representations are maintained and possibly reorganized. We hypothesize that feed-forward thalamocortical connections are an adequate site of plasticity while cortico-cortical connections are believed to drive a competitive mechanism that is critical for learning. We model a small skin patch located on the distal phalangeal surface of a digit as a set of 256 Merkel ending complexes (MEC) that feed a computational model of the primary somatosensory cortex (area 3b). This model is a two-dimensional neural field where spatially localized solutions (a.k.a. bumps) drive cortical plasticity through a Hebbian-like learning rule. Simulations explain the initial formation of ordered representations following repetitive and random stimulations of the skin patch. Skin lesions as well as cortical lesions are also studied and results confirm the possibility to reorganize representations using the same learning rule and depending on the type of the lesion. For severe lesions, the model suggests that cortico-cortical connections may play an important role in complete recovery.     

Neural basis of learning new movements: evolution of classical concepts

According to classical consepts, the role of the motor cortex in performance of skilled movements of distal parts of extremities is confined to control of appropriate motoneurons by the "point-to-point" principle. However, much evidence of plasticity of the motor cortex and its active role in motor learning appeared in last decade. Fos-gene expression in the motor cortex was found to accompany learning a skill. Strengthening of horizontal pathways in layers II-III was revealed, and cholinergic input to tese layers was found to be important. The imaging data show that activity of the motor cortex increases during motor practice as well. This raises the question of specificity of the motor cortex in the motor learning per se. During acquisition of new movements some previously used synergies prevent the necessary coordination from being learned, so they must be suppressed in the process of motor learning. Investigations of central mechanisms of coordination interference in humans are still at the beginning. However, there are some animal models of reorganization and suppression of interfering synergies. The reorganization and suppression of coordination preventing realization of a new movement is shown to be a specific function of the motor cortex. After automation of new synergies the cortical control is still present, as distinct from the learned movements, which do not require suppression of interfering synergies. However, it does not mean that the conscious control of the performance is still present.     

Lesions of the Basal Forebrain Cholinergic System in Mice Disrupt Idiothetic Navigation

Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer’s disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer’s disease patients perform poorly on both real space and computerized cued (allothetic) or uncued (idiothetic) recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze), and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer’s disease.     

Nerve growth factor increases stimulus-evoked metabolic activity in acetylcholine-depleted barrel cortex

Lesions of the basal forebrain deplete the neocortex of cholinergic fibers. Acetylcholine depletion in the somatosensory cortex of rats results in reduced stimulus-evoked activity in response to whisker stimulation. Previous studies demonstrate that embryonic basal forebrain transplants improve functional activity toward normal. It is not clear if the activity increase is due to cholinergic replacement or other factors present in the graft. In this study, we examined the possibility that nerve growth factor (NGF), a neurotrophin known as a survival factor and a specific protectant for cholinergic basal forebrain neurons, can preserve basal forebrain cells after a lesion and restore functional activity in the somatosensory cortex. We report that NGF alone is capable of restoring functional activity in the barrel cortex of animals with basal forebrain lesions, while vehicle injections of saline do not alter activity. Both high (10 mug) and low (5 mug) doses of NGF unilaterally injected into the lateral ventricle improved stimulus-evoked functional activity during bilateral whisker stimulation. The mechanism of NGF action is not clear since the restoration of functional activity in cortex was not accompanied by increased cholinergic activity as detected by acetylcholinesterase fiber staining. NGF may act directly on cortical neurons, although its site of action is not well defined.     

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: II. Cortical morphology

Previous studies in the mouse have shown that neonatal lesions to the cholinergic basal forebrain (nBM) areas result in transient cholinergic depletion of neocortex and precipitate altered cortical morphogenesis. Lesion-induced morphological alterations in cortex persist into adulthood and are accompanied by behavioral changes, including spatial memory deficits. The current study investigated whether neonatal nBM lesions affect male and female mice differently in adulthood. Quantitative morphometry of cortical layer width was employed to assess alterations in cytoarchitecture in neonatally nBM-lesioned and littermate control mice of both sexes following behavioral testing. Our results showed significant decreases in cortical layer IV and V widths across somato/motor cortex in neonatally nBM lesioned mice of both sexes. Sexually dimorphic responses were observed in cortical layer II/III and total cortical width, limited to the area containing the “barrel cortex” representation of the whisker hairs. In lesioned females, layer II/III and total cortical width were decreased relative to female controls, and in lesioned males, layer II/III was increased relative to controls, whereas total cortical width was unchanged. In male but not female mice we observed significant correlations between decreased widths in layer IV and V and impaired performance on a spatial memory task. The current data further support a role of developing cholinergic cortical afferents in the modulation of cortical morphogenesis and cortical circuits involved in cognitive behaviors. In addition, our observations provide further evidence for sexually dimorphic development and function in cognitive centers of the rodent brain. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 595–606, 1998     

The human basal forebrain integrates the old and the new

Acquisition of new learning is challenged by the phenomenon of proactive interference (PI), which occurs when previous learning disrupts later learning. Whereas human neuroimaging studies have focused on the cortical contributions to interference resolution, animal studies demonstrate that efficient resolution of PI depends on cholinergic modulation from basal forebrain (BF). Whether the BF promotes PI resolution in humans is unknown. Here, we adapted a PI paradigm from animal studies for use in a functional MRI experiment. During PI resolution, neurologically intact subjects recruited a BF network that included afferent anterior and posterior cortical sites associated with efficient memory acquisition and perceptual processing. Despite normal performance, nonamnesic patients with alcoholism, which is known to disrupt BF function, did not activate a BF network but instead invoked anterior cortical sites traditionally associated with executive function. These results provide evidence for parallel neural systems, each with the potential to resolve interference in the face of competing information.     

Cognitive functions of the basal forebrain.

Studies of the function of the basal forebrain have focused on cholinergic neurons that project to cortical and limbic structures critical for various cognitive abilities. Recent experiments suggest that these neurons serve a modulatory function in cognition, by optimizing cortical information processing and influencing attention.     

Role of corticofugal feedback in hearing

The auditory system consists of the ascending and descending (corticofugal) systems. The corticofugal system forms multiple feedback loops. Repetitive acoustic or auditory cortical electric stimulation activates the cortical neural net and the corticofugal system and evokes cortical plastic changes as well as subcortical plastic changes. These changes are short-term and are specific to the properties of the acoustic stimulus or electrically stimulated cortical neurons. These plastic changes are modulated by the neuromodulatory system. When the acoustic stimulus becomes behaviorally relevant to the animal through auditory fear conditioning or when the cortical electric stimulation is paired with an electric stimulation of the cholinergic basal forebrain, the cortical plastic changes become larger and long-term, whereas the subcortical changes stay short-term, although they also become larger. Acetylcholine plays an essential role in augmenting the plastic changes and in producing long-term cortical changes. The corticofugal system has multiple functions. One of the most important functions is the improvement and adjustment (reorganization) of subcortical auditory signal processing for cortical signal processing.     

Against memory systems

The medial temporal lobe is indispensable for normal memory processing in both human and non-human primates, as is shown by the fact that large lesions in it produce a severe impairment in the acquisition of new memories. The widely accepted inference from this observation is that the medial temporal cortex, including the hippocampal, entorhinal and perirhinal cortex, contains a memory system or multiple memory systems, which are specialized for the acquisition and storage of memories. Nevertheless, there are some strong arguments against this idea: medial temporal lesions produce amnesia by disconnecting the entire temporal cortex from neuromodulatory afferents arising in the brainstem and basal forebrain, not by removing cortex; the temporal cortex is essential for perception as well as for memory; and response properties of temporal cortical neurons make it impossible that some kinds of memory trace could be stored in the temporal lobe. All cortex is plastic, and it is possible that the same rules of plasticity apply to all cortical areas; therefore, memory traces are stored in widespread cortical areas rather than in a specialized memory system restricted to the temporal lobe. Among these areas, the prefrontal cortex has an important role in learning and memory, but is best understood as an area with no specialization of function.     

Representational plasticity in the mammalian brain cortex. (Review article)

The epithelial receptors are represented in the mammalian brain cortex in a genetically defined, strictly regulated manner. Until the 1970s, the cortical maps and the wiring of the central nervous system were thought to be rather static and unchangeable. Subsequently, however, studies of sensory and motor cortical maps in particular genetic strains of animals and in animals with different perinatal or adult histories have revealed that the map organization can be modified at any time between conception and death. Especially studies of the effects of peripheral and central lesions and of perceptual learning on the sensory and motor cortical representations have had a dramatic effect in alerting neuroscientists and therapists to the reorganizational capacity of the adult brain. From a theoretical aspect, these changes in the cortical maps provide useful models for an understanding of the changes that can occur in the integrative functions of complex brain networks throughout life.     

mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions.     

Does the destruction of the catecholaminergic neurons in newborn rat pups influence the modulatory function of the cholinergic system?]

On outbred ratlings aged 21-31 days the influence was studied of the destruction of catecholaminergic (CA) system on the reactions of the neurones of the cortical somatosensory zone, elicited by the stimulation of the ischiatic nerve and modulation of these reactions after stimulation of the basal nuclei area (the source of the neocortex cholinergic innervation) and acetylcholine (ACh) microiontophoretic application. It is shown that destruction of CA system in newborn ratlings increases the reactivity of the somatosensory cortical neurones in 21-31 days old animals to sensory stimulation; it does not influence the efficiency of modulating action of the cholinergic system of the forebrain and leads to the increase of modulating influence of the applicated ACh. It is postulated that as the result of perinatal destruction of CA brain system, in the neocortex a specific morpho-functional organization is formed of structures and processes at which the modulating function of the forebrain cholinergic system turns out, by quantitative criterion, at least, to be compensated.     

ERK is involved in the reorganization of somatosensory cortical maps in adult rats submitted to hindlimb unloading

Sensorimotor restriction by a 14-day period of hindlimb unloading (HU) in the adult rat induces a reorganization of topographic maps and receptive fields. However, the underlying mechanisms are still unclear. Interest was turned towards a possible implication of intracellular MAPK signaling pathway since Extracellular-signal-Regulated Kinase 1/2 (ERK1/2) is known to play a significant role in the control of synaptic plasticity. In order to better understand the mechanisms underlying cortical plasticity in adult rats submitted to a sensorimotor restriction, we analyzed the time-course of ERK1/2 activation by immunoblot and of cortical reorganization by electrophysiological recordings, on rats submitted to hindlimb unloading over four weeks. Immunohistochemistry analysis provided evidence that ERK1/2 phosphorylation was increased in layer III neurons of the somatosensory cortex. This increase was transient, and parallel to the changes in hindpaw cortical map area (layer IV). By contrast, receptive fields were progressively enlarged from 7 to 28 days of hindlimb unloading. To determine whether ERK1/2 was involved in cortical remapping, we administered a specific ERK1/2 inhibitor (PD-98059) through osmotic mini-pump in rats hindlimb unloaded for 14 days. Results demonstrate that focal inhibition of ERK1/2 pathway prevents cortical reorganization, but had no effect on receptive fields. These results suggest that ERK1/2 plays a role in the induction of cortical plasticity during hindlimb unloading.     

Alterations in Cortical Sensorimotor Connectivity following Complete Cervical Spinal Cord Injury: A Prospective Resting-State fMRI Study

Functional magnetic resonance imaging (fMRI) studies have demonstrated alterations during task-induced brain activation in spinal cord injury (SCI) patients. The interruption to structural integrity of the spinal cord and the resultant disrupted flow of bidirectional communication between the brain and the spinal cord might contribute to the observed dynamic reorganization (neural plasticity). However, the effect of SCI on brain resting-state connectivity patterns remains unclear. We undertook a prospective resting-state fMRI (rs-fMRI) study to explore changes to cortical activation patterns following SCI. With institutional review board approval, rs-fMRI data was obtained in eleven patients with complete cervical SCI (>2 years post injury) and nine age-matched controls. The data was processed using the Analysis of Functional Neuroimages software. Region of interest (ROI) based analysis was performed to study changes in the sensorimotor network using pre- and post-central gyri as seed regions. Two-sampled t-test was carried out to check for significant differences between the two groups. SCI patients showed decreased functional connectivity in motor and sensory cortical regions when compared to controls. The decrease was noted in ipsilateral, contralateral, and interhemispheric regions for left and right precentral ROIs. Additionally, the left postcentral ROI demonstrated increased connectivity with the thalamus bilaterally in SCI patients. Our results suggest that cortical activation patterns in the sensorimotor network undergo dynamic reorganization following SCI. The presence of these changes in chronic spinal cord injury patients is suggestive of the inherent neural plasticity within the central nervous system.