Erfahrungsgesteuerte neuronale Plastizität Bedeutung für Pathogenese und Therapie psychischer Erkrankungen

Whereas the basic wiring of the mammalian central nervous system is genetically predefined, its fine tuning throughout different phases of infancy, childhood, and adulthood are highly experience-dependent. There is growing evidence from a variety of experimental data that juvenile experience and learning events modulate the functional maturation of the brain, thereby shaping the neuronal substrate for the development of intellectual and socioemotional capacities. Since early experiences occur during phases of elevated neuronal and synaptic plasticity, they induce an "imprinting" of synaptic connectivity and neural circuitry in the infant brain. Results from experimental research support the hypothesis that impoverished intellectual stimulation and traumatic socioemotional experience during early childhood may impair the formation of functional brain pathways, in particular of the limbic circuits, which play a major role in emotional behavior and learning. Such defective systems, representing functional "scars" in the brain, may be the neuronal basis of a variety of mental disorders and clinical symptoms caused by early stressful psychosocial environments. A basic thesis of this paper is that mechanisms involved in neuronal learning and memory are not only used and reused in structuring the CNS during the initial establishment of connections in the immature brain but also can be employed in molding personality and behavior during psychotherapy in adulthood.     

The neurobiology of opiate tolerance,dependence and sensitization: Mechanisms of NMDA receptor-dependent synaptic plasticity

Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-D-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.     

Competition among multiple memory systems: converging evidence from animal and human brain studies

Research of the neurobiological bases of learning and memory suggest that these processes are not unitary in nature, but rather that relatively independent neural systems appear to mediate different types of memory. Neurobiological studies, for instance, have identified separable cognitive or "declarative" and stimulus-response "habit" memory systems that rely upon the medial temporal lobe (e.g. hippocampus) and basal ganglia (e.g. caudate-putamen), respectively. Evidence indicates that multiple memory systems are activated simultaneously and in parallel in various learning tasks, and recent findings suggest that these systems may interact. One form of interaction between medial temporal lobe and basal ganglia memory systems appears competitive in nature, and has been revealed in non-human animal studies in which damage to a given memory system results in enhanced learning. Recent human neuroimaging research has also provided evidence in favor of competition between memory systems. Thus, converging evidence across species supports the hypothesis of interactive multiple memory systems in the mammalian brain. Potential neurobiological mechanisms mediating such interactions include direct anatomical projections between the medial temporal lobe and basal ganglia, indirect neuromodulatory influences of other brain structures (e.g. basolateral amygdala) and activity of neocortical brain regions involved in top-down response selection.     

Hitting a moving target: Basic mechanisms of recovery from acquired developmental brain injury

Acquired brain injuries represent a major cause of disability in the pediatric population. Understanding responses to developmental acquired brain injuries requires knowledge of the neurobiology of normal development, age-at-injury effects and experience-dependent neuroplasticity. In the developing brain, full recovery cannot be considered as a return to the premorbid baseline, since ongoing maturation means that cerebral functioning in normal individuals will continue to advance. Thus, the recovering immature brain has to ‘hit a moving target’ to achieve full functional recovery, defined as parity with age-matched uninjured peers. This review will discuss the consequences of developmental injuries such as focal lesions, diffuse hypoxia and traumatic brain injury (TBI). Underlying cellular and physiological mechanisms relevant to age-at-injury effects will be described in considerable detail, including but not limited to alterations in neurotransmission, connectivity/network functioning, the extracellular matrix, response to oxidative stress and changes in cerebral metabolism. Finally, mechanisms of experience-dependent plasticity will be reviewed in conjunction with their effects on neural repair and recovery.     

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Numerous studies have reported that long-term musical training can affect brain functionality and induce structural alterations in the brain. Singing is a form of vocal musical expression with an unparalleled capacity for communicating emotion; however, there has been relatively little research on neuroplasticity at the network level in vocalists (i.e., noninstrumental musicians). Our objective in this study was to elucidate changes in the neural network architecture following long-term training in the musical arts. We employed a framework based on graph theory to depict the connectivity and efficiency of structural networks in the brain, based on diffusion-weighted images obtained from 35 vocalists, 27 pianists, and 33 nonmusicians. Our results revealed that musical training (both voice and piano) could enhance connectivity among emotion-related regions of the brain, such as the amygdala. We also discovered that voice training reshaped the architecture of experience-dependent networks, such as those involved in vocal motor control, sensory feedback, and language processing. It appears that vocal-related changes in areas such as the insula, paracentral lobule, supramarginal gyrus, and putamen are associated with functional segregation, multisensory integration, and enhanced network interconnectivity. These results suggest that long-term musical training can strengthen or prune white matter connectivity networks in an experience-dependent manner.     

Stronger Top-Down and Weaker Bottom-Up Frontotemporal Connections During Sensory Learning Are Associated With Severity of Psychotic Phenomena

Recent theories in computational psychiatry propose that unusual perceptual experiences and delusional beliefs may emerge as a consequence of aberrant inference and disruptions in sensory learning. The current study investigates these theories and examines the alterations that are specific to schizophrenia spectrum disorders vs those that occur as psychotic phenomena intensify, regardless of diagnosis. We recruited 66 participants: 22 schizophrenia spectrum inpatients, 22 nonpsychotic inpatients, and 22 nonclinical controls. Participants completed the reversal oddball task with volatility manipulated. We recorded neural responses with electroencephalography and measured behavioral errors to inferences on sound probabilities. Furthermore, we explored neural dynamics using dynamic causal modeling (DCM). Attenuated prediction errors (PEs) were specifically observed in the schizophrenia spectrum, with reductions in mismatch negativity in stable, and P300 in volatile, contexts. Conversely, aberrations in connectivity were observed across all participants as psychotic phenomena increased. DCM revealed that impaired sensory learning behavior was associated with decreased intrinsic connectivity in the left primary auditory cortex and right inferior frontal gyrus (IFG); connectivity in the latter was also reduced with greater severity of psychotic experiences. Moreover, people who experienced more hallucinations and psychotic-like symptoms had decreased bottom-up and increased top-down frontotemporal connectivity, respectively. The findings provide evidence that reduced PEs are specific to the schizophrenia spectrum, but deficits in brain connectivity are aligned on the psychosis continuum. Along the continuum, psychotic experiences were related to an aberrant interplay between top-down, bottom-up, and intrinsic connectivity in the IFG during sensory uncertainty. These findings provide novel insights into psychosis neurocomputational pathophysiology.     

Contexts and catalysts: a resolution of the localization and integration of function in the brain

There has been a historical tension between theories of brain function emphasizing regional specialization and those focusing on integration across regions. This tension continues despite the pervasive use of functional neuroimaging, which enables testing of these theories in the human brain. There are instances of agreement, where regions thought to be critical for a given behavior (e.g., Broca's area and language production) do become more active when a person engages in that behavior. However, a number of disconcerting results have also been found. These include activation in areas not thought to be important for the behavior, and lack of activation in regions thought to be critical for particular behaviors based on studies of the damaged brain. A recently proposed Neural Context hypothesis of brain function provides a mechanism that can reconcile these apparently disparate findings. The hypothesis states that the functional relevance of a brain area depends on the status of other connected areas i.e., the context within which the region is operating. A region can participate in several behaviors through variations in its interactions with other areas. It is possible that certain critical nodes serve as Behavioural Catalysts, enabling the transition between behavioral states, without differential alterations in the measured activity. By virtue of its anatomical connections, an area could facilitate a shift in functional connectivity between one set of regions to another. An imaging study on the changing interregional interactions involving the hippocampus in learning and awareness serves as an example of neural context. In this case, the hippocampus may serve to catalyze the transition to awareness.     

Contexts and catalysts

There has been a historical tension between theories of brain function emphasizing regional specialization and those focusing on integration across regions. This tension continues despite the pervasive use of functional neuroimaging, which enables testing of these theories in the human brain. There are instances of agreement, where regions thought to be critical for a given behavior (e.g., Broca’s area and language production) do become more active when a person engages in that behavior. However, a number of disconcerting results have also been found. These include activation in areas not thought to be important for the behavior, and lack of activation in regions thought to be critical for particular behaviors based on studies of the damaged brain. A recently proposed Neural Context hypothesis of brain function provides a mechanism that can reconcile these apparently disparate findings. The hypothesis states that the functional relevance of a brain area depends on the status of other connected areas—i.e., the context within which the region is operating. A region can participate in several behaviors through variations in its interactions with other areas. It is possible that certain critical nodes serve as Behavioural Catalysts, enabling the transition between behavioral states, without differential alterations in the measured activity. By virtue of its anatomical connections, an area could facilitate a shift in functional connectivity between one set of regions to another. An imaging study on the changing interregional interactions involving the hippocampus in learning and awareness serves as an example of neural context. In this case, the hippocampus may serve to catalyze the transition to awareness.     

Mushroom body volume is related to social aggression and ovary development in the paperwasp Polistes instabilis

The mushroom bodies (MB) are a complex neuropil in insect brains that have been implicated in higher-order information processing such as sensory integration and various types of learning and memory. Eusocial insects are excellent models to test functional neural plasticity in the MB because genetically related nest mates differ in task performance, environmental experience and social interactions. Previous research on eusocial insects shows that experience-dependent changes in brain anatomy (i.e., enlarged MB calyces) are positively correlated with task performance and social interactions. In this study, we quantified relationships of task performance and social and reproductive dominance with MB volume in Polistes instabilis, a primitively eusocial paper wasp. We used experimental removals of dominant workers to induce changes in aggressive behavior and foraging by workers. Ovary development and social dominance were positively associated with the volume of the MB calyces relative to the region containing the Kenyon cell bodies. In contrast to highly eusocial insect workers, foraging behavior was not positively correlated with MB calycal volume. We conclude that mushroom body volume is more strongly associated with dominance rank than with foraging behavior in Polistes instabilis.     

Neural plasticity and memory: towards an integrated view.

The search for the neural determinants of learning and memory has recently focused on phenomena of neural plasticity. The present paper will try to review and relate the functional significance of such specific plastic changes within neural elements to the process of learning in several species and cell types. Pioneer work proposed in simple organisms and recent emerging evidence on the role of the NMDA receptor complex and calcium-related events will be analyzed in the light of experimental findings suggesting that common biochemical events may underlie different forms of experience-dependent neural adaptation.     

Propofol disrupts functional interactions between sensory and high-order processing of auditory verbal memory

Current theories suggest that disrupting cortical information integration may account for the mechanism of general anesthesia in suppressing consciousness. Human cognitive operations take place in hierarchically structured neural organizations in the brain. The process of low-order neural representation of sensory stimuli becoming integrated in high-order cortices is also known as cognitive binding. Combining neuroimaging, cognitive neuroscience, and anesthetic manipulation, we examined how cognitive networks involved in auditory verbal memory are maintained in wakefulness, disrupted in propofol-induced deep sedation, and re-established in recovery. Inspired by the notion of cognitive binding, an functional magnetic resonance imaging-guided connectivity analysis was utilized to assess the integrity of functional interactions within and between different levels of the task-defined brain regions. Task-related responses persisted in the primary auditory cortex (PAC), but vanished in the inferior frontal gyrus (IFG) and premotor areas in deep sedation. For connectivity analysis, seed regions representing sensory and high-order processing of the memory task were identified in the PAC and IFG. Propofol disrupted connections from the PAC seed to the frontal regions and thalamus, but not the connections from the IFG seed to a set of widely distributed brain regions in the temporal, frontal, and parietal lobes (with exception of the PAC). These later regions have been implicated in mediating verbal comprehension and memory. These results suggest that propofol disrupts cognition by blocking the projection of sensory information to high-order processing networks and thus preventing information integration. Such findings contribute to our understanding of anesthetic mechanisms as related to information and integration in the brain.     

Distinct neural substrates for visual short‐term memory of actions

Fundamental theories of human cognition have long posited that the short‐term maintenance of actions is supported by one of the “core knowledge” systems of human visual cognition, yet its neural substrates are still not well understood. In particular, it is unclear whether the visual short‐term memory (VSTM) of actions has distinct neural substrates or, as proposed by the spatio‐object architecture of VSTM, shares them with VSTM of objects and spatial locations. In two experiments, we tested these two competing hypotheses by directly contrasting the neural substrates for VSTM of actions with those for objects and locations. Our results showed that the bilateral middle temporal cortex (MT) was specifically involved in VSTM of actions because its activation and its functional connectivity with the frontal–parietal network (FPN) were only modulated by the memory load of actions, but not by that of objects/agents or locations. Moreover, the brain regions involved in the maintenance of spatial location information (i.e., superior parietal lobule, SPL) was also recruited during the maintenance of actions, consistent with the temporal–spatial nature of actions. Meanwhile, the frontoparietal network (FPN) was commonly involved in all types of VSTM and showed flexible functional connectivity with the domain‐specific regions, depending on the current working memory tasks. Together, our results provide clear evidence for a distinct neural system for maintaining actions in VSTM, which supports the core knowledge system theory and the domain‐specific and domain‐general architectures of VSTM.     

Expression of dominant negative cadherin in the adult mouse brain modifies rearing behavior

The cadherin superfamily of cell-cell adhesion molecules (CAM) are crucial regulators of morphogenesis and axonal guidance during development of the nervous system and have been suggested to play important roles in neural plasticity of the brain. To study the latter, we created a mouse model that expressed a dominant negative classical cadherin in the brain of adult mice. The mice were tested for spontaneous motor activity and exploratory behavior in the open field, anxiety in the plus-maze, and spatial learning and memory in the water-T maze. Mice expressing the dominant negative cadherin displayed reduced rearing behavior, but no change in motor activity, in the open field, indicating deficits in exploratory behavior. In the water maze, animals expressing the mutant cadherin showed normal escape latencies and were indistinguishable from control littermates. Similarly, LTP in hippocampal slices of cadherin mutant and control mice were indistinguishable. These findings demonstrate intact spatial learning in mice expressing a dominant negative cadherin but altered rearing behavior, suggesting the involvement of classical cadherins in mechanisms mediating rearing behavior.     

A role for sleep in brain plasticity

The idea that sleep might be involved in brain plasticity has been investigated for many years through a large number of animal and human studies, but evidence remains fragmentary. Large amounts of sleep in early life suggest that sleep may play a role in brain maturation. In particular, the influence of sleep in developing the visual system has been highlighted. The current data suggest that both Rapid Eye Movement (REM) and non-REM sleep states would be important for brain development. Such findings stress the need for optimal paediatric sleep management. In the adult brain, the role of sleep in learning and memory is emphasized by studies at behavioural, systems, cellular and molecular levels. First, sleep amounts are reported to increase following a learning task and sleep deprivation impairs task acquisition and consolidation. At the systems level, neurophysiological studies suggest possible mechanisms for the consolidation of memory traces. These imply both thalamocortical and hippocampo-neocortical networks. Similarly, neuroimaging techniques demonstrated the experience-dependent changes in cerebral activity during sleep. Finally, recent works show the modulation during sleep of cerebral protein synthesis and expression of genes involved in neuronal plasticity.     

Neuronal networks in mental diseases and neuropathic pain: Beyond brain derived neurotrophic factor and collapsin response mediator proteins

The brain is a complex network system that has the capacity to support emotion, thought, action, learning and memory, and is characterized by constant activity, constant structural remodeling, and constant attempt to compensate for this remodeling. The basic insight that emerges from complex network organization is that substantively different networks can share common key organizational principles. Moreover, the interdependence of network organization and behavior has been successfully demonstrated for several specific tasks. From this viewpoint, increasing experimental/clinical observations suggest that mental disorders are neural network disorders. On one hand, single psychiatric disorders arise from multiple, multifactorial molecular and cellular structural/functional alterations spreading throughout local/global circuits leading to multifaceted and heterogeneous clinical symptoms. On the other hand, various mental diseases may share functional deficits across the same neural circuit as reflected in the overlap of symptoms throughout clinical diagnoses. An integrated framework including experimental measures and clinical observations will be necessary to formulate a coherent and comprehensive understanding of how neural connectivity mediates and constraints the phenotypic expression of psychiatric disorders.     

The lateral and ventromedial prefrontal cortex work as a dynamic integrated system: evidence from FMRI connectivity analysis

Recent functional magnetic resonance imaging (fMRI) investigations of the interaction between cognition and reward processing have found that the lateral prefrontal cortex (PFC) areas are preferentially activated to both increasing cognitive demand and reward level. Conversely, ventromedial PFC (VMPFC) areas show decreased activation to the same conditions, indicating a possible reciprocal relationship between cognitive and emotional processing regions. We report an fMRI study of a rewarded working memory task, in which we further explore how the relationship between reward and cognitive processing is mediated. We not only assess the integrity of reciprocal neural connections between the lateral PFC and VMPFC brain regions in different experimental contexts but also test whether additional cortical and subcortical regions influence this relationship. Psychophysiological interaction analyses were used as a measure of functional connectivity in order to characterize the influence of both cognitive and motivational variables on connectivity between the lateral PFC and the VMPFC. Psychophysiological interactions revealed negative functional connectivity between the lateral PFC and the VMPFC in the context of high memory load, and high memory load in tandem with a highly motivating context, but not in the context of reward alone. Physiophysiological interactions further indicated that the dorsal anterior cingulate and the caudate nucleus modulate this pathway. These findings provide evidence for a dynamic interplay between lateral PFC and VMPFC regions and are consistent with an emotional gating role for the VMPFC during cognitively demanding tasks. Our findings also support neuropsychological theories of mood disorders, which have long emphasized a dysfunctional relationship between emotion/motivational and cognitive processes in depression.     

Perceptual and Neural Plasticity of Odor Quality Coding in the Human Brain

Current neurobiological models of odor perception tend to emphasize the “bottom-up” contributions of odorant chemistry in determining the perceptual features of an odor. However, increasing research suggests that “top-down” effects related to learning and experience play equally important roles in human olfactory perception, implying that a given set of olfactory receptors activated by an odorant does not neatly map onto a given odor percept. Rather, odor perception may rely on more synthetic mechanisms subserved by higher order brain regions. This review article focuses on the modulatory effects of learning, context, and experience on human odor perception. Recent psychophysical and neuroimaging work from our laboratory indicates that sensory-specific information about odor quality is not static within human piriform and orbitofrontal cortices but can be rapidly updated by mere sensory exposure. This experience-dependent neural plasticity parallels behavioral improvements in odor perception, providing direct evidence for the role of learning in shaping neural representations of odor quality in the human brain.     

Perspectives on the neural the human brain connectivity of the fornix in

The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas rele- vant to cholinergic nuclei （septal forebrain region and brainstem） and memory function （medial temporal lobe）. In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix.     

Hippocampal contributions to serial‐order memory

Our memories form a record not only of our experiences, but also of their temporal structure. Although memory for the temporal structure of experience likely relies on multiple neural systems, numerous studies have implicated the hippocampus in the encoding and retrieval of temporal information. This review evaluates the literature on hippocampal contributions to human serial‐order memory from the perspective of three cognitive theories: associative chaining theory, positional‐coding theory and retrieved‐context theory. Evaluating neural findings through the lens of cognitive theories enables us to draw more incisive conclusions about the relations between brain and behavior.     

Perspectives on the neural connectivity of the fornix in the human brain

The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit.Diffusion tensor imaging enables to estimate the neural connectivity of the fornix.The anterior fornical body has high connectivity with the anterior commissure,and brain areas relevant to cholinergic nuclei(septal forebrain region and brainstem)and memory function(medial temporal lobe).In the normal subjects,by contrast,the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum.We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix.