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

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

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

New born immature neurons in the DG of the HIPP during learning.

<p>BrdU/DCX-IR cells are expressed as the mean ± sem (Panel A-E). Control (n = 10); BCIT, Box Control of IT (n = 10); IT (n = 10); BCTr, Box Control of Tr (n = 10), Tr (n = 10), BCTr₃, Box Control of Tr₃ (n = 10), Tr₃ (n = 10), BCTr_4-7, Box Control of Tr_4-7 (n = 10), Tr_4-7 (n = 10). *p<0.05,**p<0.01,***p<0.001. One way ANOVA followed by Tukey's post hoc test.</p

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

Cell proliferation and astrogliogenesisin the mPFC due to learning.

<p>PCNA-IR in the mPFC are expressed as the mean ± sem (panel A and panel F). BrdU-IR and BrdU/GFAP-IR cells in the mPFC from animals sacrificed the same day after the last BrdU injection are expressed as the mean ± sem (panel B-E). BrdU-IR and BrdU/GFAP-IR cells in the mPFC from animals sacrificed one week after the last BrdU injection are expressed as the mean ± sem (panel G-J). BrdU/GFAP-IR cells from IT₁, IT, Tr and Tr₁ groups are are expressed as the mean ± sem (panel K-N). Control₁ (n = 10); BCIT₁, Box Control of IT₁ (n = 10); IT₁ (n = 10); BCTr₁, Box Control of Tr₁ (n = 10), Tr₁ (n = 10), Control (n = 10); BCIT, Box Control of IT (n = 10); IT (n = 10); BCTr, Box Control of Tr (n = 10), Tr (n = 10). *p<0.05,**p<0.01,***p<0.001. One way ANOVA followed by Tukey's post hoc test.</p

Differential cell proliferation and BrdU incorporation in the DG of the HIPP during learning.

<p>PCNA-IR in the HIPP are expressed as the mean ± sem (panel A-B). BrdU-IR -IR cells among experimental groups in the HIPP are expressed as the mean ± sem (Panel C-G).. Control₁ (n = 10); BCIT₁, Box Control of IT₁ (n = 10); IT₁ (n = 10); BCTr₁, Box Control of Tr₁ (n = 10), Tr₁ (n = 10); Control (n = 10); BCIT, Box Control of IT (n = 10); IT (n = 10); BCTr, Box Control of Tr (n = 10), Tr (n = 10); BCTr₃, Box Control of Tr₃ (n = 10), Tr₃ (n = 10), BCTr_4-7, Box Control of Tr_4-7 (n = 10), Tr4-7 (n = 10). *p<0.05,**p<0.01,***p<0.001. One way ANOVA followed by Tukey's post hoc test.</p