Homeostatic plasticity is important to maintain a set level of activity in neuronal circuits and has been most extensively studied in cell cultures following activity blockade. It is still unclear, ...however, whether activity changes associated with mechanisms of homeostatic plasticity occur in vivo, for example after changes in sensory input. Here, we show that activity levels in the visual cortex are significantly decreased after sensory deprivation by retinal lesions, followed by a gradual increase in activity levels in the 48 hr after deprivation. These activity changes are associated with synaptic scaling, manifested in vitro by an increase in mEPSC amplitude and in vivo by an increase in spine size. Together, these data show that homeostatic activity changes occur in vivo in parallel with synaptic scaling.
•Deprivation results in compensatory homeostatic increases in spine size in vivo•Neuronal activity in the visual cortex drops after complete removal of visual input•Activity levels are restored in the 48 hr after visual deprivation•Ex vivo measurements show increased spine size is paralleled by synaptic scaling
Keck et al. investigate homeostatic plasticity in the mouse visual cortex in vivo and find that cortical activity levels decrease after visual deprivation and gradually recover in the subsequent 48 hr, accompanied by a corresponding increase in synaptic strength.
A fundamental property of neuronal circuits is the ability to adapt to altered sensory inputs. It is well established that the functional synaptic changes underlying this adaptation are reflected by ...structural modifications in excitatory neurons. In contrast, the degree to which structural plasticity in inhibitory neurons accompanies functional changes is less clear. Here, we use two-photon imaging to monitor the fine structure of inhibitory neurons in mouse visual cortex after deprivation induced by retinal lesions. We find that a subset of inhibitory neurons carry dendritic spines, which form glutamatergic synapses. Removal of visual input correlates with a rapid and lasting reduction in the number of inhibitory cell spines. Similar to the effects seen for dendritic spines, the number of inhibitory neuron boutons dropped sharply after retinal lesions. Together, these data suggest that structural changes in inhibitory neurons may precede structural changes in excitatory circuitry, which ultimately result in functional adaptation following sensory deprivation.
► Chronic two-photon imaging of inhibitory neurons in mouse visual cortex ► A small subset of inhibitory neurons has dendritic spines with excitatory synapses ► Spine density in these neurons decreases by 30% within 72 hr of a retinal lesion ► After a retinal lesion, inhibitory bouton density decreases by 20% within 72 hr
Adult visual plasticity underlying local remodeling of the cortical circuitry in vivo appears to be associated with a spatiotemporal pattern of strongly increased spontaneous and evoked activity of ...populations of cells. Here we review and discuss pioneering work by us and others about principles of plasticity in the adult visual cortex, starting with our study which showed that a confined lesion in the cat retina causes increased excitability in the affected region in the primary visual cortex accompanied by fine-tuned restructuring of neuronal function. The underlying remodeling processes was further visualized with voltage-sensitive dye (VSD) imaging that allowed a direct tracking of retinal lesion-induced reorganization across horizontal cortical circuitries. Nowadays, application of noninvasive stimulation methods pursues the idea further of increased cortical excitability along with decreased inhibition as key factors for the induction of adult cortical plasticity. We used high-frequency transcranial magnetic stimulation (TMS), for the first time in combination with VSD optical imaging, and provided evidence that TMS-amplified excitability across large pools of neurons forms the basis for noninvasively targeting reorganization of orientation maps in the visual cortex. Our review has been compiled on the basis of these four own studies, which we discuss in the context of historical developments in the field of visual cortical plasticity and the current state of the literature. Overall, we suggest markers of LTP-like cortical changes at mesoscopic population level as a main driving force for the induction of visual plasticity in the adult. Elevations in excitability that predispose towards cortical plasticity are most likely a common property of all cortical modalities. Thus, interventions that increase cortical excitability are a promising starting point to drive perceptual and potentially motor learning in therapeutic applications.
Transcranial magnetic stimulation (TMS) has become a popular clinical method to modify cortical processing. The events underlying TMS-induced functional changes remain, however, largely unknown ...because current noninvasive recording methods lack spatiotemporal resolution or are incompatible with the strong TMS-associated electrical field. In particular, an answer to the question of how the relatively unspecific nature of TMS stimulation leads to specific neuronal reorganization, as well as a detailed picture of TMS-triggered reorganization of functional brain modules, is missing. Here we used real-time optical imaging in an animal experimental setting to track, at submillimeter range, TMS-induced functional changes in visual feature maps over several square millimeters of the brain’s surface. We show that high-frequency TMS creates a transient cortical state with increased excitability and increased response variability, which opens a time window for enhanced plasticity. Visual stimulation (i.e., 30 min of passive exposure) with a single orientation applied during this TMS-induced permissive period led to enlarged imprinting of the chosen orientation on the visual map across visual cortex. This reorganization was stable for hours and was characterized by a systematic shift in orientation preference toward the trained orientation. Thus, TMS can noninvasively trigger a targeted large-scale remodeling of fundamentally mature functional architecture in early sensory cortex.
Significance Transcranial magnetic stimulation (TMS) is significant for medical diagnostics, therapeutic treatment, and basic brain research. However, highly resolved observations of its immediate ...effects remained obscured because existing techniques are limited in spatial or temporal resolutions and are severely disturbed by the high magnetic fields. Here, we avoid these limitations, using optical imaging with voltage-sensitive dye (VSD) in the cat animal model. VSD transforms changes in neuronal membrane voltage into optical signals, providing microsecond resolution and evading contamination by electromagnetic artifacts. We visualize TMS-induced cortical dynamics and characterize effects on visual processing over scales of milliseconds, minutes, and hours. Combined TMS and VSD imaging offers a powerful approach to study targeted modifications in cortical function during TMS-based plasticity and learning protocols.
Mitochondria buffer intracellular Ca2+ and provide energy 1. Because synaptic structures with high Ca2+ buffering 2–4 or energy demand 5 are often localized far away from the soma, mitochondria are ...actively transported to these sites 6–11. Also, the removal and degradation of mitochondria are tightly regulated 9, 12, 13, because dysfunctional mitochondria are a source of reactive oxygen species, which can damage the cell 14. Deficits in mitochondrial trafficking have been proposed to contribute to the pathogenesis of Parkinson’s disease, schizophrenia, amyotrophic lateral sclerosis, optic atrophy, and Alzheimer’s disease 13, 15–19. In neuronal cultures, about a third of mitochondria are motile, whereas the majority remains stationary for several days 8, 20. Activity-dependent mechanisms cause mitochondria to stop at synaptic sites 7, 8, 20, 21, which affects synapse function and maintenance. Reducing mitochondrial content in dendrites decreases spine density 22, 23, whereas increasing mitochondrial content or activity increases it 7. These bidirectional interactions between synaptic activity and mitochondrial trafficking suggest that mitochondria may regulate synaptic plasticity. Here we investigated the dynamics of mitochondria in relation to axonal boutons of neocortical pyramidal neurons for the first time in vivo. We find that under these circumstances practically all mitochondria are stationary, both during development and in adulthood. In adult visual cortex, mitochondria are preferentially localized at putative boutons, where they remain for several days. Retinal-lesion-induced cortical plasticity increases turnover of putative boutons but leaves mitochondrial turnover unaffected. We conclude that in visual cortex in vivo, mitochondria are less dynamic than in vitro, and that structural plasticity does not affect mitochondrial dynamics.
•In neocortex in vivo, very few axonal mitochondria are motile•Mitochondria stay put longer when localized close to an axonal bouton•Structural plasticity in visual cortex does not alter axonal mitochondrial turnover
Mitochondria are actively transported in axons and influence synaptic function and plasticity. Using two-photon microscopy, Smit-Rigter, Rajendran et al. find that, surprisingly, axonal mitochondria in developing and adult neocortex in vivo are much less motile than in culture, and that structural plasticity does not affect mitochondrial turnover.
Human cortical excitability can be modified by repetitive transcranial magnetic stimulation (rTMS), but the cellular mechanisms are largely unknown. Here, we show that the pattern of delivery of ...theta-burst stimulation (TBS) (continuous versus intermittent) differently modifies electric activity and protein expression in the rat neocortex. Intermittent TBS (iTBS), but not continuous TBS (cTBS), enhanced spontaneous neuronal firing and EEG gamma band power. Sensory evoked cortical inhibition increased only after iTBS, although both TBS protocols increased the first sensory response arising from the resting cortical state. Changes in the cortical expression of the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) indicate that changes in spontaneous and evoked cortical activity following rTMS are in part related to altered activity of inhibitory systems. By reducing PV expression in the fast-spiking interneurons, iTBS primarily affected the inhibitory control of pyramidal cell output activity, while cTBS, by reducing CB expression, more likely affected the dendritic integration of synaptic inputs controlled by other classes of inhibitory interneurons. Calretinin, the third major calcium-binding protein expressed by another class of interneurons was not affected at all. We conclude that different patterns of TBS modulate the activity of inhibitory cell classes differently, probably depending on the synaptic connectivity and the preferred discharge pattern of these inhibitory neurons.
The cerebral cortex has the ability to adapt to altered sensory inputs. In the visual cortex, a small lesion to the retina causes the deprived cortical region to become responsive to adjacent parts ...of the visual field. This extensive topographic remapping is assumed to be mediated by the rewiring of intracortical connections, but the dynamics of this reorganization process remain unknown. We used repeated intrinsic signal and two-photon imaging to monitor functional and structural alterations in adult mouse visual cortex over a period of months following a retinal lesion. The rate at which dendritic spines were lost and gained increased threefold after a small retinal lesion, leading to an almost complete replacement of spines in the deafferented cortex within 2 months. Because this massive remodeling of synaptic structures did not occur when all visual input was removed, it likely reflects the activity-dependent establishment of new cortical circuits that serve the recovery of visual responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The mammalian central nervous system (CNS) is characterized by a severely limited regeneration capacity. Comparison with lower species like amphibians, which are able to restore even complex tissues ...after damage, indicates the presence of an inhibitory environment that restricts the cellular response in mammals. In this context, signals provided by the extracellular matrix (ECM) are important regulators of events like cell survival, proliferation, migration, differentiation or neurite outgrowth. Therefore, knowledge of the postlesional ECM and cells that produce these factors might support development of new treatment strategies for patients suffering from traumatic brain injury and other types of CNS damage. In the present study, we analyzed the surround of focal infrared laser lesions of the adult mouse visual cortex. This lesion paradigm avoids direct contact with the brain as the laser beam passes the intact bone. Cell type-specific markers revealed a distinct spatial distribution of different astroglial subtypes in the penumbra after injury. Glial fibrillary acidic protein (GFAP) as marker for reactive astrocytes was found broadly up-regulated, whereas cells coexpressing GFAP and the more immature markers vimentin and nestin were only expressed by a subset of cells. Dividing astrocytes could be identified via the proliferation marker Ki-67. Different ECM molecules, among others the neural stem cell-associated glycoprotein tenascin-C and the DSD-1 chondroitin sulfate epitope, were found on astrocytes in the penumbra. Wisteria floribunda agglutinin (WFA) and aggrecan as markers for perineuronal nets, a specialized ECM limiting synaptic plasticity, appeared normal in the vicinity of the necrotic lesion core. In sum, expression of progenitor markers by astrocyte subpopulations and the identification of proliferating astrocytes in combination with an ECM that contains components typically associated with neural stem/progenitor cells suggest that an immature cell fate is facilitated as response to the injury.
Highlights • Cortical feature preferences arise from seeds of subcortical origin. • The cortical selectivity results from inhibition that sharpens biases of thalamic input. • This process also leads ...to the creation of cortical orientation columns. • Our scheme also explains the formation of ocular dominance columns and ON/OFF domains.
PDF
