Renata Zakrzewska

Brain activation patterns during classical conditioning with appetitive or aversive UCS.

The neural bases of appetitive and aversive conditioning are different, and at various stages of learning, may engage distinct cortical and subcortical networks. Using [14C]2-deoxyglucose (2-DG) autoradiography, we examined brain activation in mice during the first and the third sessions of a classical conditioning involving stimulation of whiskers on one side of the muzzle (conditioned stimulus, CS) paired with an aversive or appetitive unconditioned stimulus (UCS). The nucleus basalis magnocellularis showed stronger labelling during appetitive conditioning while the lateral hypothalamus was activated only during aversive pairing session. Also, in the appetitive training (both conditioning and pseudoconditioning), the ventral pallidum responded differently than in the aversive situation. A tendency for higher labelling of basolateral amygdala was noted in aversive conditioning. Somatosensory thalamic nuclei, as well as posterior parietal cortex and nucleus accumbens core, were strongly activated in both conditions during the first training session, but only by appetitive conditioning during the third session. With the exception of the nucleus basalis, ventral pallidum and lateral hypothalamus, appetitive or aversive classical conditioning increased 2-DG uptake in a similar set of brain structures. Activation of nucleus accumbens core, posterior parietal cortex, and structures of the somatosensory pathway decreases with the duration of training presumably due to different involvement of attention and different dynamics of the two variants of conditioning.

Reduced plasticity of cortical whisker representation in adult tenascin-C-deficient mice after vibrissectomy

The effect of the extracellular matrix recognition molecule tenascin‐C on cerebral plasticity induced by vibrissectomy was investigated with 2‐deoxyglucose (2DG) brain mapping in tenascin‐C‐deficient mice. Unilateral vibrissectomy sparing row C of vibrissae was performed in young adult mice. Two months later, cortical representations of spared row C vibrissae and control row C on the other side of the snout were visualized by [14C]2DG autoradiography. In both wild‐type and tenascin‐C‐deficient mice, cortical representation of the spared row was expanded in all layers of the barrel cortex. However, the effect was significantly more extensive in wild‐type animals than in the mutant. Elimination of tenascin‐C by genetic manipulation thus reduces the effect of vibrissectomy observed in the somatosensory cortex. No increase in number of fibres in the vibrissal nerve of spared vibrissae was seen, and occurrence of additional nerve to the spared follicle was very rare. Thus, in tenascin‐C‐deficient mice functional plasticity seems to be impaired within the CNS.

Impairment of experience-dependent cortical plasticity in aged mice

This study addresses the relationship between aging and experience-dependent plasticity in the mouse somatosensory cortex. Plasticity in the cortical representation of vibrissae (whiskers) was investigated in young (3 months), mature (14 months) and old (2 years) mice using [14C]2-deoxyglucose (2-DG) autoradiography. Plastic changes were evoked using two experimental paradigms. The deprivation-based protocol included unilateral deprivation of all but one row of whiskers for a week. In the conditioning protocol the animals were subjected to classical conditioning, where tactile stimulation of one row of whiskers was paired with an aversive stimulus. Both procedures evoked functional plasticity in the young group, expressed as a widening of the functional cortical representation of the spared or conditioned row. Aging had a differential effect on these two forms of plasticity. Conditioning-related plasticity was more vulnerable to aging: the plastic change was not detectable in mature animals, even though they acquired the behavioral response. Deprivation-induced plasticity also declined with age, but some effects were persistent in the oldest animals.

Functional assessment of sensory functions after photothrombotic stroke in the barrel field of mice

Motor, sensory and cognitive deficits are common impairments observed in human stroke as well as in animal stroke models. Using a battery of behavioural tests we assessed sensorimotor deficits after photothrombotic stroke localized within or beyond cortical representation of mouse sensory vibrissae. We found restricted, modality specific behavioural consequences in the acute post-stroke period. Among incorporated tests, adhesive removal test, novelty exploration test and sensory labyrinth task were sensitive to the somatosensory cortical deficits. Injured animals explored new objects significantly longer, they also needed distinctly more time to contact and to remove the adhesive tape placed on whiskers contralateral to the infarct. Moreover, we observed that after stroke animals were unable to solve the sensory labyrinth depending only upon tactile sensation from whiskers with injured cortical representation. Spontaneous recovery could be observed within the first post-stroke week for adhesive tape removal and within 14 days for labyrinth performance. However, for the novel object exploration we did not observed the recovery for the period of 18 days after stroke. Moreover, new object exploration test performance differed between the somatosensory and visual cortical impairments. We suggest that those three tests might be valuable in assessing the usefulness of therapies designed to support brain repair after experimental stroke.

Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission

Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning-induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response.

Associative pairing involving monocular stimulation selectively mobilizes a subclass of GABAergic interneurons in the mouse visual cortex

Levels of γ‐aminobutyric acid (GABA) and its synthesizing enzyme in cerebral cortex are regulated by sensory experience. Previously we found that associative pairing of vibrissae stimulation and tail shock results in upregulation of GABAergic markers in the mouse barrel cortex. In order to ascertain whether GABAergic upregulation also accompanies associative pairing in other sensory modalities, we examined the mouse visual cortex after analogous training with visual stimulus. During pairing, visual stimulus (CS) was coupled with a tail shock (UCS). We examined the density of cells expressing glutamic acid decarboxylase (GAD) and parvalbumin (PV) in monocular and binocular segments of the primary visual cortex (V1). The auditory cortex was used as a control. After monocular training, the density of cells expressing GAD rose significantly in the monocular segment of V1 contralateral to the stimulated eye, compared with the opposite hemisphere. This effect was due to the association of CS and UCS, as no changes were found after visual stimulation alone or in the auditory cortex. No changes were noted in the density of PV+ neurons, so the effect was attributed to GAD+/PV− neurons. Mobilization of a specific subclass of GABAergic cells, observed after associative pairing in the somatosensory and visual cortices, may reflect the necessity to restrict the activity of circuits involved in sensory association. J. Comp. Neurol. 516:482–492, 2009.

Inhibition of Tnf-α R1 signaling can rescue functional cortical plasticity impaired in early post-stroke period.

Tumor necrosis factor-α (TNF-α) is one of the key players in stroke progression and can interfere with brain functioning. We previously documented an impairment of experience-dependent plasticity in the cortex neighboring the stroke-induced lesion, which was accompanied with an upregulation of Tnf-α level in the brain of ischemic mice 1 week after the stroke. Because TNF receptor 1 (TnfR1) signaling is believed to be a major mediator of the cytotoxicity of Tnf-α through activation of caspases, we used an anti-inflammatory intervention aimed at Tnf-α R1 pathway, in order to try to attenuate the detrimental effect of post-stroke inflammation, and investigated if this will be effective in protecting plasticity in the infarct proximity. Aged mice (12-14 months) were subjected to the photothrombotic stroke localized near somatosensory cortex, and immediately after ischemia sensory deprivation was introduced to induce plasticity. Soluble TNF-α R1 (sTNF-α R1), which competed for TNF-α with receptors localized in the brain, was delivered chronically directly into the brain tissue for the whole period of deprivation using ALZET Micro-Osmotic pumps. We have shown that such approach undertaken simultaneously with the stroke reduced the level of TNF-α in the peri-ischemic tissue and was successful in preserving the post-stroke deprivation-induced brain plasticity.

Attentional deficits and altered neuronal activation in medial prefrontal and posterior parietal cortices in mice with reduced dopamine transporter levels

ABSTRACT The executive control function of attention is regulated by the dopaminergic (DA) system. Dopamine transporter (DAT) likely plays a role in controlling the influence of DA on cognitive processes. We examined the effects of DAT depletion on cognitive processes related to attention. Mice with the DAT gene genetically deleted (DAT+/− heterozygotes) were compared to wild type (WT) mice on the Attentional Set‐Shifting Task (ASST). Changes in neuronal activity during the ASST were shown with early growth response genes 1 and 2 (egr‐1 and egr‐2) immunohistochemistry in the medial prefrontal cortex (mPFC) and in the posterior parietal cortex (PPC). Heterozygotes were impaired in tasks that tax reversal learning, attentional‐set formation and set‐shifting. Densities of egr‐2 labeled cells in the mPFC were lower in mutant mice when compared with wild‐types in intradimensional shift of attention (IDS), extradimensional shift of attention and extradimensional shift of attention‐reversal phases of the ASST task, and in PPC in the IDS phase of the task. The results demonstrate impairments of the areas associated with attentional functions in DAT+/− mice and show that an imbalance of the dopaminergic system has an impact on the complex attention‐related executive functions. HighlightsThe effects of DAT depletion on cognitive processes related to attention were studied.Imbalance of the dopaminergic system impacts attention‐related executive functions.Attentional deficits are accompanied by a lower activation of neurons in the IL, PrL and PPC regions.

Correlated activation of the thalamocortical network in a simple learning paradigm.

The thalamocortical loop is a key player in sensory processing. We examined the functional interactions among its elements, expressed as cross-correlations between metabolic activity of the barrel cortex, somatosensory thalamic nuclei and posterior parietal cortex, in classical conditioning. In the training stimulation of vibrissae in mice was paired with a tail shock. [14C]-2-Deoxyglucose brain mapping was performed during the first and the final sessions of conditioning (conditioned stimulus+unconditioned stimulus; CS+UCS), in groups that received only the stimulation of vibrissae (conditioned stimulus; CS-only) and in nonstimulated controls (NS). In the CS-only group, the CS evoked the correlated activity of the examined structures during the first session, but in the third session these structures did not act in a correlated manner. Conversely, in the CS+UCS condition correlations among the thalamocortical loop structures activities became stronger during the course of the training. Particularly, the posterior parietal cortex, which controls voluntary deployment of attention, together with the barrel cortex becomes involved in the network of structures with the correlated activity. The results suggest a predominant role for bottom-up processing in the somatosensory pathway at the beginning of conditioning followed by top-down processing. This is consistent with the idea that the thalamocortical loop plays a crucial role in attentional processes.