Plasticity in the Rat Prefrontal Cortex: Linking Gene Expression and an Operant Learning with a Computational Theory

The plasticity in the medial Prefrontal Cortex (mPFC) of rodents or lateral prefrontal cortex in non human primates (lPFC), plays a key role neural circuits involved in learning and memory. Several genes, like brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Synapsin I, Calcium/calmodulin-dependent protein kinase II (CamKII), activity-regulated cytoskeleton-associated protein (Arc), c-jun and c-fos have been related to plasticity processes. We analysed differential expression of related plasticity genes and immediate early genes in the mPFC of rats during learning an operant conditioning task. Incompletely and completely trained animals were studied because of the distinct events predicted by our computational model at different learning stages. During learning an operant conditioning task, we measured changes in the mRNA levels by Real-Time RT-PCR during learning; expression of these markers associated to plasticity was incremented while learning and such increments began to decline when the task was learned. The plasticity changes in the lPFC during learning predicted by the model matched up with those of the representative gene BDNF. Herein, we showed for the first time that plasticity in the mPFC in rats during learning of an operant conditioning is higher while learning than when the task is learned, using an integrative approach of a computational model and gene expression

White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology

INTRODUCTION: An inactivating mutation in the MATERIALS AND METHODS: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in RESULTS: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain DISCUSSION: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. Th

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain’s resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues

Antidepressants: Influence on cancer and immunity?

Two decades ago, it was hypothesized that antidepressants could alter the course of neoplastic diseases. However, contradictory findings indicated that antidepressants could either have carcinogenic properties or improve the disease outcome. Intriguingly, controversial results were reported on the action of antidepressant drugs on immune function. Further hypotheses proposed that antidepressants could indirectly affect the cancer prognosis through the modulation of antitumor activity. Here we review the literature in order to elucidate the influence of antidepressants on cancer and immunity.Fil: Frick, Luciana Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Rapanelli, Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina

Wrestling and Wrapping: A Perspective on SUMO Proteins in Schwann Cells

Schwann cell development and peripheral nerve myelination are finely orchestrated multistep processes; some of the underlying mechanisms are well described and others remain unknown. Many posttranslational modifications (PTMs) like phosphorylation and ubiquitination have been reported to play a role during the normal development of the peripheral nervous system (PNS) and in demyelinating neuropathies. However, a relatively novel PTM, SUMOylation, has not been studied in these contexts. SUMOylation involves the covalent attachment of one or more small ubiquitin-like modifier (SUMO) proteins to a substrate, which affects the function, cellular localization, and further PTMs of the conjugated protein. SUMOylation also regulates other proteins indirectly by facilitating non-covalent protein–protein interaction via SUMO interaction motifs (SIM). This pathway has important consequences on diverse cellular processes, and dysregulation of this pathway has been reported in several diseases including neurological and degenerative conditions. In this article, we revise the scarce literature on SUMOylation in Schwann cells and the PNS, we propose putative substrate proteins, and we speculate on potential mechanisms underlying the possible involvement of this PTM in peripheral myelination and neuropathies

Microglial Dysregulation in Psychiatric Disease

Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy

Learning an operant conditioning task differentially induces gliogenesis in the medial prefrontal cortex and neurogenesis in the hippocampus.

Circuit modification associated with learning and memory involves multiple events, including the addition and remotion of newborn cells trough adulthood. Adult neurogenesis and gliogenesis were mainly described in models of voluntary exercise, enriched environments, spatial learning and memory task; nevertheless, it is unknown whether it is a common mechanism among different learning paradigms, like reward dependent tasks. Therefore, we evaluated cell proliferation, neurogenesis, astrogliogenesis, survival and neuronal maturation in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP) during learning an operant conditioning task. This was performed by using endogenous markers of cell proliferation, and a bromodeoxiuridine (BrdU) injection schedule in two different phases of learning. Learning an operant conditioning is divided in two phases: a first phase when animals were considered incompletely trained (IT, animals that were learning the task) when they performed between 50% and 65% of the responses, and a second phase when animals were considered trained (Tr, animals that completely learned the task) when they reached 100% of the responses with a latency time lower than 5 seconds. We found that learning an operant conditioning task promoted cell proliferation in both phases of learning in the mPFC and HIPP. Additionally, the results presented showed that astrogliogenesis was induced in the medial prefrontal cortex (mPFC) in both phases, however, the first phase promoted survival of these new born astrocytes. On the other hand, an increased number of new born immature neurons was observed in the HIPP only in the first phase of learning, whereas, decreased values were observed in the second phase. Finally, we found that neuronal maturation was induced only during the first phase. This study shows for the first time that learning a reward-dependent task, like the operant conditioning, promotes neurogenesis, astrogliogenesis, survival and neuronal maturation depending on the learning phase in the mPFC-HIPP circuit

Different MK-801 administration schedules induce mild to severe learning impairments in an operant conditioning task: role of buspirone and risperidone in ameliorating these cognitive deficits

Blockade of N-methyl-d-aspartate receptor (NMDA) by the noncompetitive NMDA receptor (NMDAR) antagonist MK-801 produces behavioral abnormalities and alterations in prefrontal cortex (PFC) functioning. Due to the critical role of the PFC in operant conditioning task learning, we evaluated the effects of acute, repeated postnatal injections of MK-801 (0.1 mg/kg) on learning performance. We injected Long-Evans rats i.p. with MK-801 (0.1 mg/kg) using three different administration schedules: injection 40 min before beginning the task (during) (n = 12); injection twice daily for six consecutive days prior to beginning the experimental procedures (prior) (n = 12); or twice daily subcutaneous injections from postnatal day 7 to 11 (postnatal) (n = 12). Next, we orally administered risperidone (serotonin receptor 2A and dopamine receptor 2 antagonist, 1 mg/kg) or buspirone (serotonin receptor 1A partial agonist, 10 mg/kg) to animals treated with the MK-801 schedule described above. The postnatal and prior administration schedules produced severe learning deficits, whereas injection of MK-801 just before training sessions had only mild effects on acquisition of an operant conditioning. Risperidone was able to reverse the detrimental effect of MK-801 in the animals that were treated with MK-801 during and prior training sessions. In contrast, buspirone was only effective at mitigating the cognitive deficits induced by MK-801 when administered during the training procedures. The data demonstrates that NMDA antagonism disrupts basic mechanisms of learning in a simple PFC-mediated operant conditioning task, and that buspirone and risperidone failed to attenuate the learning deficits when NMDA neurotransmission was blocked in the early stages of the postnatal period.Fil: Rapanelli, Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Frick, Luciana Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Bernardez Vidal, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Zanutto, Bonifacio Silvano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina

Illustration of phenotypic analysis of new born cells in the mPFC and HIPP.

<p>Double positive cells for BrdU (green) and GFAP (red) in the prelimbic region of mPFC from animals of the IT group (panel A and B). BrdU-IR cells (red) stained with DCX (green) in the granule cell layer of the HIPP (panel C and D) from animals of Tr₃ group. New born mature neuron marked with NeuN (green) and BrdU (red) in the DG of the HIPP (panel E and F) from animals of Tr group. Arrowhead in each image points to a double positive cell for BrdU/NeuN, BrdU/DCX and BrdU/GFAP. PCNA-IR in the in the prelimbic region of mPFC from animals of the Tr group (panel G). Bar scales for A, C and E panels indicate 20 µm. Bar scale for G panel indicates 10 µm.</p