Experience-dependent structural plasticity in the cortex

Synapses are the fundamental units of neuronal circuits. Synaptic plasticity can occur through changes in synaptic strength, as well as through the addition/removal of synapses. Two-photon microscopy in combination with fluorescence labeling offers a powerful tool to peek into the living brain and follow structural reorganization at individual synapses. Time-lapse imaging depicts a dynamic picture in which experience-dependent plasticity of synaptic structures varies between different cortical regions and layers, as well as between neuronal subtypes. Recent studies have demonstrated that the formation and elimination of synaptic structures happens rapidly in a subpopulation of cortical neurons during various sensorimotor learning experiences, and that stabilized synaptic structures are associated with long lasting memories for the task. Therefore, circuit plasticity, mediated by structural remodeling, provides an underlying mechanism for learning and memory.     

Monoaminergic afferents to the neocortex: a developmental histofluorescence study in normal and Reeler mouse embryos

The patterns of distribution of monoaminergic (MA) afferents during early histogenesis of the neocortex of normal and Reeler mice are studied by histofluorescence microscopy. Fluorescing fibers appear rostrally in the cortex of both genotypes on the 14th embryonic day (E14), which is within 24 h of the development of the cortical plate. They are distributed to all regions of the cortex by the time of birth. Although the patterns of intracortical deployment differ in the two genotypes, the fibers appear to have homologous target structures. These are: (1) the polymorphic cells of the subplate in the depths of the normal and in the superplate near the surface of the mutant cortex; and (2) the zones of consolidation of apical dendrites of pyramidal cells: the external plexiform zone of normal and a series of intracortical plexiform planes in the mutant cortex. By contrast, the axons of this system do not branch significantly among the compactly ordered somata of pyramidal cells within the cortical plate of either genotype.     

Experience-dependent structural plasticity in cortex heterotopic to focal sensorimotor cortical damage

Structural plasticity following focal neocortical damage in adult rats has recently been found to be sensitive to postinjury rehabilitative training. Experience on a complex motor skills task, the acrobatic task, after unilateral lesions of the forelimb representation region of the sensorimotor cortex (FLsmc) enhanced synaptic structural changes in the cortex contralateral and homotopic to the lesions. Using tissue from this previous study, the present study examined whether a heterotopic region of the sensorimotor cortex of either hemisphere, the hindlimb representation area (HLsmc), would undergo structural changes following unilateral FLsmc lesions and whether these changes would also be sensitive to postinjury training on the acrobatic task. Stereological methods for light and electron microscopy were used to assess structural changes in lesion or sham-operated rats following 28 days of postoperative acrobatic training or simple repetitive exercise (motor controls). In the HLsmc contralateral to the lesions of rats receiving acrobatic training, there was a subtle, but significant, increase in cortical volume and in layer II/III neuropil and dendritic volume per neuron in comparison to shams. In rats receiving simple exercise after the lesions, these changes were not significantly different from shams. Acrobatic training also prevented a loss of cortical volume in the HLsmc adjacent to the lesion in comparison to shams. These data suggest that behavioral training following cortical injury facilitates structural plasticity in behaviorally relevant areas of the neocortex other than the homotopic cortex contralateral to the lesion. This structural plasticity might be relevant to the development of behavioral compensation after cortical injury.     

Anatomical correlates of functional plasticity in mouse visual cortex

Much of what is known about activity-dependent plasticity comes from studies of the primary visual cortex and its inputs in higher mammals, but the molecular bases remain largely unknown. Similar functional plasticity takes place during a critical period in the visual cortex of the mouse, an animal in which genetic experiments can readily be performed to investigate the underlying molecular and cellular events. The experiments of this paper were directed toward understanding whether anatomical changes accompany functional plasticity in the developing visual cortex of the mouse, as they do in higher mammals. In normal mice, transneuronal label after an eye injection clearly delineated the monocular and binocular zones of area 17. Intrinsic signal optical imaging also showed monocular and binocular zones of area 17 but revealed no finer organization of ocular dominance or orientation selectivity. In normal animals, single geniculocortical afferents serving the contralateral eye showed great heterogeneity and no clustering consistent with the presence of ocular dominance patches. Growth and elaboration of terminal arbor continues beyond postnatal day 40 (P40), after the peak of the critical period. After prolonged monocular deprivation (MD) from P20 to P60, transneuronal labeling showed that the projection serving the ipsilateral eye was severely affected, whereas the effect on the contralateral eye's pathway was inconsistent. Optical imaging also showed profound effects of deprivation, particularly in the ipsilateral pathway, and microelectrode studies confirmed continued functional plasticity past P40. Reconstruction of single afferents showed that MD from P20 to P40 promoted the growth of the open eye's geniculocortical connections without causing the closed eye's contralateral projection to shrink, whereas MD from P20 to P60 caused an arrest of growth of deprived arbors. Our findings reveal numerous similarities between mouse and higher mammals in development and plasticity, along with some differences. We discuss the factors that may be responsible for these differences.     

Identification of multisegmental nociceptive afferents that modulate locomotor circuits in the neonatal mouse spinal cord

Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin‐sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin‐sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4‐evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870–2887, 2013. © 2013 Wiley Periodicals, Inc.     

Nongeniculate afferents to striate cortex in macaques

Horseradish peroxidase (HRP) was injected in relatively massive amounts to cover most, or portions, of opercular striate cortex in four macaques. Absence of transcallosal or circumventricular labelling, plus discrete and consistent retrograde labelling in other areas in the four cases, assured the validity and specificity of the observations. Numerous labelled cells in regions directly bordering striate cortex, however, were excluded from the analysis because of the possibility of uptake consequent to physical diffusion. With this exception, all labelled cells were counted at roughly 2-mm intervals for one case with extensive unilateral injection of HRP. Even excluding the closely circumstriate population, the totals indicate that more than 30% of the afferent input to striate cortex arises from nongeniculate sources. Four areas of neocortex together make up about one-fourth of the total afferents: superior temporal sulcus 17.1%; inferior occipital area, 6.1%; intraparietal sulcus, 0.4%; and parahippocampal gyrus, 0.3%. Other areas projecting to striate cortex include claustrum, pulvinar, nucleus paracentralis, raphé system, locus coeruleus, and the nucleus basalis of Meynert. Cells of the latter were particularly striking with their very heavy uptake of HRP, and, even in cases of minimal effective injection, were scattered throughout an extensive area from the posterior edge of the globus pallidus passing rostrally beyond the chiasm and into the nucleus of the diagonal band. On the basis of their distribution and known cholinergic affinity, it is argued that this group also includes the cells labelled in and around lateral hypothalamus and cerebral peduncle, and that as a whole the group constitutes a cholinergic counterpart of the diffusely projecting monoaminergic systems. It seems possible that the basalis projection at first follows a fornical-subcallosal pathway to reach striate cortex via callosoperforant fibers.     

Imaging of experience-dependent structural plasticity in the mouse neocortex in vivo

The functionality of adult neocortical circuits can be altered by novel experiences or learning. This functional plasticity appears to rely on changes in the strength of neuronal connections that were established during development. Here we will describe some of our studies in which we have addressed whether structural changes, including the remodeling of axons and dendrites with synapse formation and elimination, could underlie experience-dependent plasticity in the adult neocortex. Using 2-photon laser-scanning microscopes and transgenic mice expressing GFP in a subset of pyramidal cells, we have observed that a small subset of dendritic spines continuously appear and disappear on a daily basis, whereas the majority of spines persists for months. Axonal boutons from different neuronal classes displayed similar behavior, although the extent of remodeling varied. Under baseline conditions, new spines in the barrel cortex were mostly transient and rarely survived for more than a week. However, when every other whisker was trimmed, the generation and loss of persistent spines was enhanced. Ultrastructural reconstruction of previously imaged spines and boutons showed that new spines slowly form synapses. New spines persisting for a few days always had synapses, whereas very young spines often lacked synapses. New synapses were predominantly found on large, multi-synapse boutons, suggesting that spine growth is followed by synapse formation, preferentially on existing boutons. Altogether our data indicate that novel sensory experience drives the stabilization of new spines on subclasses of cortical neurons and promotes the formation of new synapses. These synaptic changes likely underlie experience-dependent functional remodeling of specific neocortical circuits.     

Organization of afferents to the orbitofrontal cortex in the rat

The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas.     

Monoaminergic modulation of emotional impact in the inferomedial prefrontal cortex

People assess the impact of emotionally loaded images differently. We define this impact as the average difference between individual ratings of standardized “pleasant” and “unpleasant” images. To determine the neuroanatomical correlate of a hypothetical interaction between emotional impact and cerebral excitability, we first determined the individual effect on cerebral blood flow of a pharmacological challenge with the monoamine reuptake inhibitor clomipramine in nine healthy volunteers. In a later, independent, session the nine volunteers rated pleasant, neutral, and unpleasant images of the standard Empathy Picture System on a scale from +3 to ?3. We then used regression analysis to identify sites in the ventromedial prefrontal cortex at which the two separately acquired measures, blood flow change and emotional impact of images, correlated significantly. The regression analysis identified a locus in Brodmann's area 11 of the inferomedial prefrontal cortex (IMPC) at which these two separate measures had significant inverse correlation. Thus, under the specific circumstance of positron emission tomography (PET) of a pharmacological challenge, a key region of the inferomedial prefrontal cortex underwent deactivation in proportion to a separately rated emotional impact of a stimulus. We propose a specific pharmacodynamic mechanism that explains the correlation between the emotional impact and the effect of a serotonin‐noradrenaline reuptake inhibitor on cerebral blood flow. Synapse 63:160–166, 2009. © 2008 Wiley‐Liss, Inc.     

Termination of lesion-induced plasticity in the mouse barrel cortex in the absence of oligodendrocytes

Termination of developmental plasticity occurs at specific points in development, and the mechanisms responsible for it are not well understood. One hypothesis that has been proposed is that oligodendrocytes (OLs) play an important role. Consistent with this, we found that OLs appeared in the mouse somatosensory cortex at the end of the critical period for whisker lesion-induced barrel structural plasticity. To test this hypothesis, we used two mouse lines with defective OL differentiation: Olig1-deficient and jimpy. In Olig1-deficient mice, although OLs were totally absent, the termination of lesion-induced plasticity was not delayed. The timing was normal even when the cytoarchitectonic barrel formation was temporarily blocked by pharmacological treatment in Olig1-deficient mice. Furthermore, the termination was not delayed in jimpy mice. These results demonstrate that, even though OLs appear at the end of the critical period, OLs are not intrinsically necessary for the termination of lesion-induced plasticity. Our findings underscore a mechanistic distinction between the termination of thalamocortical axonal plasticity in the barrel cortex and that in the visual cortex, in which OL-derived Nogo-A/B was recently suggested to be essential.     

Monoaminergic agents modulate antidepressant-like effect caused by diphenyl diselenide in rats

In this study, the antidepressant-like effect caused by diphenyl diselenide on rat forced swimming test (FST) was investigated. The involvement of the monoaminergic system in the antidepressant-like effect was also evaluated. Diphenyl diselenide (0.1-30 mg/kg), given by oral route (p.o.), 30 min earlier, reduced the immobility time in the FST, without accompanying changes in ambulation when assessed in an open field. The anti-immobility effect of diphenyl diselenide (1 mg/kg, p.o.) on the FST was prevented by pretreatment of rats with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis, given once a day, for 3 consecutive days), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT(2A)/(2C) receptor antagonist), ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist), haloperidol (1 mg/kg, i.p., a D(1), D(2) and D(3) receptor antagonist), SCH233390 (0.05 mg/kg, s.c., a D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist). However, the anti-immobility effect caused by diphenyl diselenide (1 mg/kg, p.o.) on the FST was not affected by pretreatment with propanolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist). Furthermore, monoamine oxidase (MAO) activity was inhibited (39%) in the animals treated with diphenyl diselenide (30 mg/kg, p.o.) when compared to the control group. Taken together these data demonstrated that the antidepressant-like effect caused by diphenyl diselenide seems to be mediated by involvement of the central monoaminergic system.     

Monoaminergic compensation in the neuropeptide Y deficient mouse brain

Neuropeptide Y (NPY) is an important central regulator of food consumption and energy expenditure via the hypothalamus. NPY containing neurons have a broad central distribution and are often colocalized with norepinephrine (NE). However, NPY deficient mice do not exhibit any substantial changes in food consumption, body weight or body composition when compared to wild type mice. Since NE and serotonin (5HT) are also important regulators of appetite and metabolism, we evaluated these systems in NPY deficient mice. Brain sections from NPY deficient and wild type mice were labeled with either (3)H-nisoxetine for the NE transporter (NET) or (3)H-citalopram for the 5HT transporter (SERT). Tyrosine hydroxylase expression was evaluated by radioimmunohistochemistry. Brain monoamines and metabolites were evaluated using HPLC. NPY deficient mice exhibited a substantial decrease in NET binding in most brain regions examined. NET binding was less than 50% of control binding in the cerebral cortex and subregions of the thalamus with the greatest decrease seen in the hypothalamus. In contrast, more modest and regionally variable changes were observed in the SERT binding with decreases in regions such as the accessory olfactory nucleus, glomerular layer of the olfactory bulb and the CA1 region of the hippocampus. Measurement of NE and 5HT content as well as the primary metabolites revealed increased NE turnover and decreased 5HT content in the hypothalamus. Therefore, developmental compensation by the NE and 5HT systems may contribute to the absence of a body weight phenotype in NPY deficient mice.     

Projection of phrenic nerve afferents to the cat sensorimotor cortex

The projection of phrenic nerve afferents to the sensorimotor cortex was studied in cats. The results of these experiments demonstrate that stimulation of phrenic nerve afferents elicits cortical evoked potentials (CEPs) in the sensorimotor cortex of cats. Cortical foci for CEPs classified as primary were found in areas 3b, 3a and 4 gamma. These foci were located medial to forelimb and lateral to hindlimb afferent representations in the sensorimotor cortex.     

Monoaminergic modulation of the sensitivity of neurones in the cingulate cortex to iontophoretically applied substance P

The interactions of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) with substance P (SP) were studied on single neurones in the anterior cingulate cortex of the rat. Iontophoretic application of 5-HT potentiated the excitatory responses of some neurones to SP and reduced responses of others. However these effects were usually accompanied by parallel changes in baseline firing rate i.e. increase and decrease respectively. In studies where carbachol (CCh) was used as a control the excitatory responses to this substance were always altered in a similar fashion to those to SP. The effects of NA on SP-responses were more consistent. This amine caused a reduction of response to SP regardless of whether there was an increase, decrease, or no change in baseline firing rate. Responses to SP could be reduced on many cells in the absence of changes in response to CCh and even on some cells where CCh responses were concurrently enhanced. Lesions of the locus coeruleus which resulted in a depletion of NA in the ipsilateral cingulate cortex gave rise to a substantial increase in sensitivity of neurones to SP two weeks later. However, lesions of the median raphe(MR)-nucleus which strongly reduced cortical 5-HT had no detectable effect on SP-responses. The data indicate that both NA and 5-HT can alter cortical neurone-sensitivity to SP but that the former amine may be involved in a more specific and possibly a functional interaction.     

Voltage-dependent L-type calcium channels in the development and plasticity of mouse barrel cortex.

Entry of calcium ions into the neuron is a triggering signal for initiation of several processes which may lead to modification of synaptic connectivity. The developmental changes of voltage-dependent L-type calcium channel (VDLCC) were studied using [3H]PN 200 110 nifedipine displaceable binding in the barrel cortex of mice, a model structure for studying cortical plasticity. In vitro binding autoradiography was used to examine quantitatively the pattern of [3H]PN 200 110 binding to brains of animals aged from 3 to 70 days. The binding values in the somatosensory cortex rose two-fold in the period examined, reaching a plateau in the 4th postnatal week. The laminar pattern of binding changed during development, with the locus of heaviest labeling shifting from layer IV to II/III in the third postnatal week and thin bands of labeling developing in layers IV and VI. A very faint barrel-like pattern of labeling in the barrel field was observed. Neither this pattern nor the binding values were altered by unilateral neonatal removal of all vibrissal follicles. Saturation studies of binding to crude synaptosomal fractions of cerebral cortex of mice aged 3, 15, 28 and 70 days revealed the presence of a single binding site, with Bmax increasing from 48.7 +/- 5.1 fmol/mg protein at postnatal day 3 to 191.7 +/- 9.6 fmol/mg protein at day 70. No developmental changes in KD values were found. No correlation was found between the critical period for cytoarchitectonic plasticity of the barrels and the time when high values of VDLCC binding were observed.     

Neonatal electrolytic lesions of the basal forebrain stunt plasticity in mouse barrel field cortex

Previous studies have shown that neonatal electrolytic lesions of basal forebrain cholinergic projections in mice lead to a transient cholinergic depletion of neocortex and to permanent alterations in cortical cytoarchitecture and in cognitive performance. The present study examines whether neonatal electrolytic lesions of the basal forebrain modify neocortical plasticity. Using cytochrome oxidase histochemistry, we compared cross-sectional areas of individual barrels in the barrel field of four groups of postnatal day 8 (P8) old mice that on P1 received either (1) right electrolytic lesions of the basal forebrain, (2) left C row 1-4 whisker follicle ablations, (3) combined lesion treatments or (4) ice anesthesia only. The size of barrels in basal forebrain lesioned animals was not significantly different from controls. However, the plastic response to whisker removal was compromised in basal forebrain lesioned animals. An index of plasticity, the ratio of row D/row C areas, was reduced significantly in the combined nBM lesioned/follicle ablation group. Compared to whisker-lesioned mice, the expansion in rows B and D and the shrinkage in the lesioned row C area were diminished in the combined treatment group. The present findings correspond to those from a study of rats injected with a cholinergic immunotoxin [Cereb. Cortex 8 (1998) 63]. These results suggest that cholinergic inputs play a role in regulating plasticity as well as in the morphogenesis of mouse sensory-motor cortex.     

Long-term changes in short-interval intracortical facilitation modulate motor cortex plasticity and L-dopa-induced dyskinesia in Parkinson's disease

BackgroundAbnormal glutamatergic neurotransmission in the primary motor cortex (M1) contributes to Parkinson's disease (PD) pathophysiology and is related to l-dopa-induced dyskinesia (LID). We previously showed that short-term treatment with safinamide, a monoamine oxidase type-B inhibitor with anti-glutamatergic properties, improves abnormally enhanced short-interval intracortical facilitation (SICF) in PD patients.ObjectiveTo examine whether a long-term SICF modulation has beneficial effects on clinical measures, including LID severity, and whether these changes parallel improvement in cortical plasticity mechanisms in PD.MethodsWe tested SICF in patients with and without LID before (S0) and after short- (14 days - S1) and long-term (12 months - S2) treatment with safinamide 100 mg/day. Possible changes in M1 plasticity were assessed using intermittent theta-burst stimulation (iTBS). Finally, we correlated safinamide-related neurophysiological changes with modifications in clinical scores.ResultsSICF was enhanced at S0, and prominently in patients with LID. Safinamide normalized SICF at S1, and this effect persisted at S2. Impaired iTBS-induced plasticity was present at S0 and safinamide restored this alteration at S2. There was a significant correlation between the degree of SICF and the amount of iTBS-induced plasticity at S0 and S2. In patients with LID, the degree of SICF at S0 and S2 correlated with long-term changes in LID severity.ConclusionsAltered SICF contributes to M1 plasticity impairment in PD. Both SICF and M1 plasticity improve after long-term treatment with safinamide. The abnormality in SICF-related glutamatergic circuits plays a role in LID pathophysiology, and its long-term modulation may prevent LID worsening over time.     

Multiple sensory afferents to ferret pseudosylvian sulcal cortex

While the ferret cerebral cortex is being used with increasing frequency in studies of neural processing and development, little is known regarding the organization of its associational sensory and multisensory regions. Therefore, the present investigation used neuroanatomical methods to identify non-primary visual and somatosensory representations and their potential for multisensory convergence. Tracer injections made into V1 or SI cortex labeled axon terminals within the pseudosylvian sulcal cortex (PSSC). These inputs were distributed according to modality, with visual inputs identified in the lateral aspects of the posterior dorsal bank, and somatosensory inputs found anterior along the dorsal bank, fundus and ventral bank. Somatosensory inputs showed a topographic arrangement, with inputs representing face found more anteriorly than those representing trunk regions. Overlap between these different sensory projections occurred posteriorly in the PSSC and may represent a zone of multisensory convergence. These data are consistent with the presence of associational visual, somatosensory, and multisensory areas within the PSSC.