Pyramidal Cell Layer Research Articles

Spatiotemporal Progression of Microcalcification in the Hippocampal CA1 Region following Transient Forebrain Ischemia in Rats: An Ultrastructural Study.

Calcification in areas of neuronal degeneration is a common finding in several neuropathological disorders including ischemic insults. Here, we performed a detailed examination of the onset and spatiotemporal profile of calcification in the CA1 region of the hippocampus, where neuronal death has been observed after transient forebrain ischemia. Histopathological examinations showed very little alizarin red staining in the CA1 pyramidal cell layer until day 28 after reperfusion, while prominent alizarin red staining was detected in CA1 dendritic subfields, particularly in the stratum radiatum, by 14 days after reperfusion. Electron microscopy using the osmium/potassium dichromate method and electron probe microanalysis revealed selective calcium deposits within the mitochondria of degenerating dendrites at as early as 7 days after reperfusion, with subsequent complete mineralization occurring throughout the dendrites, which then coalesced to form larger mineral conglomerates with the adjacent calcifying neurites by 14 days after reperfusion. Large calcifying deposits were frequently observed at 28 days after reperfusion, when they were closely associated with or completely engulfed by astrocytes. In contrast, no prominent calcification was observed in the somata of CA1 pyramidal neurons showing the characteristic features of necrotic cell death after ischemia, although what appeared to be calcified mitochondria were noted in some degenerated neurons that became dark and condensed. Thus, our data indicate that intrahippocampal calcification after ischemic insults initially occurs within the mitochondria of degenerating dendrites, which leads to the extensive calcification that is associated with ischemic injuries. These findings suggest that in degenerating neurons, the calcified mitochondria in the dendrites, rather than in the somata, may serve as the nidus for further calcium precipitation in the ischemic hippocampus.

In Vitro Investigation of Synaptic Plasticity.

A classical in vitro model for investigation of information storage in the brain is based on the acute hippocampal slice. Here, repeated high-frequency stimulation of excitatory Schaeffer collaterals making synapses onto pyramidal cells in the hippocampal CA1 region leads to strengthening of evoked field-recording responses-long-term potentiation (LTP)-in keeping with Hebb's postulate. This model remains tremendously influential for its reliability, specificity, and relative ease of use. More recent plasticity studies have explored various other brain regions including the neocortex, which often requires more laborious whole-cell recordings of synaptically connected pairs of neurons, to ensure that the identities of recorded cells are known. In addition, with this experimental approach, the spiking activity can be controlled with millisecond precision, which is necessary for the study of spike-timing-dependent plasticity (STDP). Here, we provide protocols for in vitro study of hippocampal CA1 LTP using field recordings, and of STDP in synaptically connected pairs of layer-5 pyramidal cells in acute slices of rodent neocortex.

Reduced Glutamatergic Currents and Dendritic Branching of Layer 5 Pyramidal Cells Contribute to Medial Prefrontal Cortex Deactivation in a Rat Model of Neuropathic Pain.

Multiple studies have demonstrated that neuropathic pain is associated with major reorganization in multiple brain areas. In line with the strong emotional salience of chronic pain, involvement of the limbic system appears particularly important. Within the past few years, it has become clear that the functional deactivation of the prefrontal cortex (PFC) is critical for both the cognitive/emotional and the sensory components of pain. However, at the cellular level, details of this deactivation remain in large part unclear. Here we show that 1 week after a peripheral neuropathic injury (Spared Nerve Injury model) pyramidal cells in layer 5 (L5) of the rat medial PFC show responses to excitatory glutamatergic inputs that are reduced by about 50%, as well as reduced frequency of spontaneous excitatory synaptic currents. Additionally, these cells have reduced membrane capacitance and increased input resistance. All these findings are consistent with decreased dendritic length, thus we performed a detailed morphological analysis on a subset of the recorded neurons. We found that the apical dendrites proximal to the soma (excluding the tuft) are shorter and less complex in SNI animals, in agreement with the reduced capacitance and glutamatergic input. Finally, we used in vivo microdialysis to compare the basal concentrations of glutamate and GABA in the PFC of sham and SNI rats and found that ambient glutamate is decreased in SNI rats. Taken together, these data show that impaired glutamatergic transmission contributes to the functional deactivation of the mPFC in neuropathic pain. Additionally, the reduced branching of apical dendrites of L5 pyramidal neurons may underlay the gray matter reduction in chronic pain.

Enhanced expression of the calcium-sensing receptor in reactive astrocytes following ischemic injury in vivo and in vitro

We recently demonstrated that the G protein-coupled calcium-sensing receptor (CaSR) is associated with the pathogenesis of ischemic stroke and may be involved in vascular remodeling and astrogliosis. To further substantiate the involvement of CaSR in the astroglial reaction common to ischemic insults, we investigated the temporal and cell type-specific expression patterns of CaSR in the hippocampus after transient forebrain ischemia. CaSR was constitutively expressed in neurons of the pyramidal and granule cell layers, whereas increased CaSR immunoreactivity was observed in reactive astrocytes, but not in activated microglia or macrophages, in the CA1 region of the post-ischemic hippocampus. Astroglial induction of CaSR expression was evident on days 3–7 after reperfusion and appeared to increase progressively through day 28, at which time CaSR expression was prominent in astrocytes with a highly reactive hypertrophic phenotype and elevated levels of glial fibrillary acidic protein. This expression pattern was supported by results of immunoblot analyses. Furthermore, CaSR expression was upregulated in rat primary cortical astrocytes exposed to oxygen–glucose deprivation, which undergo reactive gliosis-like changes. Thus, our results demonstrate that selective and long-lasting astroglial induction of CaSR expression is a common characteristic of ischemic injury and suggest its involvement in the ischemia-induced astroglial reaction.

Repeated exposure to amphetamine during adolescence alters inhibitory tone in the medial prefrontal cortex following drug re-exposure in adulthood

Behavioral sensitization following repeated amphetamine (AMPH) exposure is associated with changes in GABA function in the medial prefrontal cortex (mPFC). In rats exposed to AMPH during adolescence compared to adulthood, there are unique patterns of sensitization that may reflect age-dependent differences in drug effects on prefrontal GABAergic function. In the current study, we used a sensitizing regimen of repeated AMPH exposure in adolescent and adult rats to determine if a post-withdrawal AMPH challenge would alter inhibitory transmission in the mPFC in a manner that depends on age of exposure. Male Sprague-Dawley rats were treated with saline or 3mg/kg AMPH (i.p.) during adolescence [postnatal day (P) 27–P45] or adulthood (P85– P103) and were sacrificed either at similar ages in adulthood (∼P133; experiment 1) or after similar withdrawal times (3–4 weeks; experiment 2). Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in vitro from deep layer pyramidal cells in the mPFC using the whole-cell configuration. We found no effect of AMPH pre-exposure on baseline sIPSC frequency. Subsequent application of AMPH (25μM) produced a stable increase in sIPSC frequency in controls, suggesting that AMPH increases inhibitory tone in the mPFC. However, AMPH failed to increase sIPSCs in adolescent- or adult-exposed rats. In experiment 2, where withdrawal period was kept similar for both exposure groups, AMPH induced a suppression of sIPSC activity in adolescent-exposed rats. These results suggest that sensitizing treatment with AMPH during adolescence or adulthood dampens inhibitory influences on mPFC pyramidal cells, but potentially through different mechanisms.

A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria.

The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice.

Exposure to a diet high in fat attenuates dendritic spine density in the medial prefrontal cortex.

A key factor in the development of obesity is the overconsumption of food calorically high in fat. Overconsumption of food high in fat not only promotes weight gain but elicits changes in reward processing. No studies to date have examined whether consumption of a high-fat (HF) diet alters structural plasticity in brain areas critical for reward processing, which may account for persistent changes in behavior and psychological function by reorganizing synaptic connectivity. To test whether dietary fat may induce structural plasticity we placed rats on one of three dietary conditions: ad libitum standard chow (SC), ad libitum 60% HF (HF-AL), or calorically matched 60% HF (HF-CM) for 3weeks and then quantified dendritic spine density and type on basal and apical dendrites of pyramidal cells in layer V of the medial prefrontal cortex (mPFC) and medium spiny neurons (MSNs) of the nucleus accumbens. Our results demonstrate a significant reduction in the density of thin spines on the apical and basal segments of dendrites within the infralimbic, but not prelimbic, mPFC.

Regional expression and ultrastructural localization of EphA7 in the hippocampus and cerebellum of adult rat.

EphA7 is expressed in the adult central nervous system (CNS), where its roles are yet poorly defined. We mapped its distribution using in situ hybridization (ISH) and immunohistochemistry (IHC) combined with light (LM) and electron microscopy (EM) in adult rat and mouse brain. The strongest ISH signal was in the hippocampal pyramidal and granule cell layers. Moderate levels were detected in habenula, striatum, amygdala, the cingulate, piriform and entorhinal cortex, and in cerebellum, notably the Purkinje cell layer. The IHC signal distribution was consistent with ISH results, with transport of the protein to processes, as exemplified in the hippocampal neuropil layers and weakly stained pyramidal cell layers. In contrast, in the cerebellum, the Purkinje cell bodies were the most strongly immunolabeled elements. EM localized the cell surface-expression of EphA7 essentially in postsynaptic densities (PSDs) of dendritic spines and shafts, and on some astrocytic leaflets, in both hippocampus and cerebellum. Perikaryal and dendritic labeling was mostly intracellular, associated with the synthetic and trafficking machineries. Immunopositive vesicles were also observed in axons and axon terminals. Quantitative analysis in EM showed significant differences in the frequency of labeled elements between regions. Notably, labeled dendrites were ∼3-5 times less frequent in cerebellum than in hippocampus, but they were individually endowed with ∼10-40 times higher frequencies of PSDs, on their shafts and spines. The cell surface localization of EphA7, being preferentially in PSDs, and in perisynaptic astrocytic leaflets, provides morphologic evidence that EphA7 plays key roles in adult CNS synaptic maintenance, plasticity, or function. J. Comp. Neurol. 524:2462-2478, 2016. © 2016 Wiley Periodicals, Inc.

Cannabinoid Control of Learning and Memory through HCN Channels

The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

Roles of specific Kv channel types in repolarization of the action potential in genetically identified subclasses of pyramidal neurons in mouse neocortex.

The action potential (AP) is a fundamental feature of excitable cells that serves as the basis for long-distance signaling in the nervous system. There is considerable diversity in the appearance of APs and the underlying repolarization mechanisms in different neuronal types (reviewed in Bean BP. Nat Rev Neurosci 8: 451-465, 2007), including among pyramidal cell subtypes. In the present work, we used specific pharmacological blockers to test for contributions of Kv1, Kv2, or Kv4 channels to repolarization of single APs in two genetically defined subpopulations of pyramidal cells in layer 5 of mouse somatosensory cortex (etv1 and glt) as well as pyramidal cells from layer 2/3. These three subtypes differ in AP properties (Groh A, Meyer HS, Schmidt EF, Heintz N, Sakmann B, Krieger P. Cereb Cortex 20: 826-836, 2010; Guan D, Armstrong WE, Foehring RC. J Neurophysiol 113: 2014-2032, 2015) as well as laminar position, morphology, and projection targets. We asked what the roles of Kv1, Kv2, and Kv4 channels are in AP repolarization and whether the underlying mechanisms are pyramidal cell subtype dependent. We found that Kv4 channels are critically involved in repolarizing neocortical pyramidal cells. There are also pyramidal cell subtype-specific differences in the role for Kv1 channels. Only Kv4 channels were involved in repolarizing the narrow APs of glt cells. In contrast, in etv1 cells and layer 2/3 cells, the broader APs are partially repolarized by Kv1 channels in addition to Kv4 channels. Consistent with their activation in the subthreshold range, Kv1 channels also regulate AP voltage threshold in all pyramidal cell subtypes.

Imaging mass spectrometry detects dynamic changes of phosphatidylcholine in rat hippocampal CA1 after transient global ischemia

Background and purpose: The initial steps in the cascade leading to cell death are still unknown because of the limitations of the existing methodology, strategy, and modalities used. Methods: Imaging mass spectrometry (IMS) was used to measure dynamic molecular changes of phosphatidylcholine (PC) species in the rat hippocampus after transient global ischemia (TGI) for 6min. Fresh frozen sections were obtained after euthanizing the rats on Days 1, 2, 4, 7, 10, 14, and 21. Histopathology and IMS of adjacent sections compared morphological and molecular changes, respectively. Results: Histopathological changes were absent immediately after TGI (at Day 1, superacute phase). At Days 2–21 after TGI (from subacute to chronic phases), histopathology revealed neuronal death associated with gliosis, inflammation, and accumulation of activated microglia in CA1. IMS detected significant molecular changes after TGI in the same CA1 domain: increase of PC (diacyl-16:0/22:6) in the superacute phase and increase of PC (diacyl-16:0/18:1) in the subacute to chronic phases. Conclusions: Histopathology and IMS can provide comprehensive and complementary information on cell death mechanisms in the hippocampal CA1 after global ischemia. IMS provided novel data on molecular changes in phospholipids immediately after TGI. Increased level of PC (diacyl-16:0/22:6) in the pyramidal cell layer of hippocampal CA1 prior to the histopathological change may represent an early step in delayed neuronal death mechanisms.

Psychedelics.

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain's default mode network.

Slow synaptic transmission mediated by TRPV1 channels in CA3 interneurons of the hippocampus

Metabotropic glutamate receptors (mGluRs) modulate various neuronal functions in the central nervous system. Many studies reported that mGluRs have linkages to neuronal disorders such as schizophrenia and autism related disorders, indicating that mGluRs are involved in critical functions of the neuronal circuits. To study this possibility further, we recorded mGluR-induced synaptic responses in the interneurons of the CA3 stratum radiatum using rat hippocampal organotypic slice cultures. Electrical stimulation in the CA3 pyramidal cell layer evoked a slow inward current in the interneurons at a holding potential of −70mV in the presence of antagonists for AMPA/kainate receptors, NMDA receptors, GABAA receptors and GABAB receptors. The slow inward current was blocked in the absence of extracellular calcium, suggesting that this was a synaptic response. The slow excitatory postsynaptic current (EPSC) reversed near 0mV, reflecting an increase in a non-selective cationic conductance. The slow EPSC is mediated by group I mGluRs, as it was blocked by AP3, a group I mGluR antagonist. Neither a calcium chelator BAPTA nor a phospholipase C (PLC) inhibitor U73122 affected the slow EPSC. La3+, a general TRP channel blocker or capsazepine, a selective TRPV1 channel antagonist significantly suppressed the slow EPSC. DHPG, a selective group I mGluRs agonist induced an inward current, which was suppressed by capsazepine. These results indicate that in the interneurons of the hippocampal CA3 stratum radiatum group I mGluRs activate TRPV1 channels independently of PLC and intracellular Ca2+, resulting in the slow EPSC in the interneurons.

Layer Specific Development of Neocortical Pyramidal to Fast Spiking Cell Synapses.

All cortical neurons are engaged in inhibitory feedback loops which ensure excitation-inhibition balance and are key elements for the development of coherent network activity. The resulting network patterns are strongly dependent on the strength and dynamic properties of these excitatory-inhibitory loops which show pronounced regional and developmental diversity. Therefore we compared the properties and postnatal maturation of two different synapses between rat neocortical pyramidal cells (layer 2/3 and layer 5, respectively) and fast spiking (FS) interneurons in the corresponding layer. At P14, both synapses showed synaptic depression upon repetitive activation. Synaptic release properties between layer 2/3 pyramidal cells and FS cells were stable from P14 to P28. In contrast, layer 5 pyramidal to FS cell connections showed a significant increase in paired pulse ratio by P28. Presynaptic calcium dynamics also changed at these synapses, including sensitivity to exogenously loaded calcium buffers and expression of presynaptic calcium channel subtypes. These results underline the large variety of properties at different, yet similar, synapses in the neocortex. They also suggest that postnatal maturation of the brain goes along with increasing differences between synaptically driven network activity in layer 5 and layer 2/3.

Electroacupuncture Ameliorates Learning and Memory and Improves Synaptic Plasticity via Activation of the PKA/CREB Signaling Pathway in Cerebral Hypoperfusion.

Electroacupuncture (EA) has shown protective effects on cognitive decline. However, the underlying molecular mechanisms are ill-understood. The present study was undertaken to determine whether the cognitive function was ameliorated in cerebral hypoperfusion rats following EA and to investigate the role of PKA/CREB pathway. We used a rat 2-vessel occlusion (2VO) model and delivered EA at Baihui (GV20) and Dazhui (GV14) acupoints. Morris water maze (MWM) task, electrophysiological recording, Golgi silver stain, Nissl stain, Western blot, and real-time PCR were employed. EA significantly (1) ameliorated the spatial learning and memory deficits, (2) alleviated long-term potentiation (LTP) impairment and the reduction of dendritic spine density, (3) suppressed the decline of phospho-CREB (pCREB) protein, brain-derived neurotrophic factor (BDNF) protein, and microRNA132 (miR132), and (4) reduced the increase of p250GAP protein of 2VO rats. These changes were partially blocked by a selective protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89), suggesting that the PKA/CREB pathway is potentially involved in the effects of EA. Moreover, any significant damage to the pyramidal cell layer of CA1 subregion was absent. These results demonstrated that EA could ameliorate learning and memory deficits and alleviate hippocampal synaptic plasticity impairment of cerebral hypoperfusion rats, potentially mediated by PKA/CREB signaling pathway.

The hippocampus participates in a pharmacological rat model of absence seizures

ObjectiveUsing the gamma-butyrolactone (GBL) model of absence seizures in Long–Evans rats, this study investigated if 2.5–6Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs. MethodsLocal field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 area. In separate experiments, multiple unit recordings were made at the hippocampal CA1 pyramidal cell layer, or the mid-septotemporal hippocampus was inactivated by local infusion of GABAA receptor agonist muscimol. ResultsAs PDs developed following GBL injection, coherence of local field potentials at 2.5–6Hz increased between the hippocampus and thalamus, and between the hippocampus and the neocortex. Hippocampal theta rhythm was disrupted when GBL induced immobility in the rats. The probability of hippocampal multiple unit firing significantly increased at 40–80ms prior to the negative peak of thalamic PDs. Coherence between hippocampal multiple unit activity and thalamic field potentials at 2.5–6Hz was significantly increased after GBL injection. Muscimol infusion to inactivate the mid-septotemporal hippocampus, as compared to saline infusion, significantly decreased the peak frequency of the PDs induced by GBL, decreased 30–120Hz hippocampal gamma power, and hastened the transition of PDs to 1–2Hz slow waves. SignificanceDuring GBL induced 2.5–6Hz PDs, a hallmark of absence seizure, increased synchronization between the hippocampus and the thalamocortical network was indicated by frequency and temporal correlation analysis. These results suggest that the hippocampus was entrained by thalamocortical activity in the present model of absence seizures. Prolonged synchronization of the hippocampus may result in synaptic alterations that may explain the cognitive and memory deficits in some patients with absence seizures and absence status epilepticus.

How a (sub)Cellular Coincidence Detection Mechanism Featuring Layer-5 Pyramidal Cells May Help Produce Various Visual Phenomena.

Perceptual phenomena such as spatio-temporal illusions and masking are typically explained by psychological (cognitive) processing theories or large-scale neural theories involving inter-areal connectivity and neural circuits comprising of hundreds or more interconnected single cells. Subcellular mechanisms are hardly used for such purpose. Here, a mechanistic theoretical view is presented on how a subcellular brain mechanism of integration of presynaptic signals that arrive at different compartments of layer-5 pyramidal neurons could explain a couple of spatiotemporal visual-phenomenal effects unfolding along very brief time intervals within the range of the sub-second temporal scale.

Sprouty2 and -4 hypomorphism promotes neuronal survival and astrocytosis in a mouse model of kainic acid induced neuronal damage.

ABSTRACTSprouty (Spry) proteins play a key role as negative feedback inhibitors of the Ras/Raf/MAPK/ERK pathway downstream of various receptor tyrosine kinases. Among the four Sprouty isoforms, Spry2 and Spry4 are expressed in the hippocampus. In this study, possible effects of Spry2 and Spry4 hypomorphism on neurodegeneration and seizure thresholds in a mouse model of epileptogenesis was analyzed. The Spry2/4 hypomorphs exhibited stronger ERK activation which was limited to the CA3 pyramidal cell layer and to the hilar region. The seizure threshold of Spry2/4+/− mice was significantly reduced at naive state but no difference to wildtype mice was observed 1 month following KA treatment. Histomorphological analysis revealed that dentate granule cell dispersion (GCD) was diminished in Spry2/4+/− mice in the subchronic phase after KA injection. Neuronal degeneration was reduced in CA1 and CA3 principal neuron layers as well as in scattered neurons of the contralateral CA1 and hilar regions. Moreover, Spry2/4 reduction resulted in enhanced survival of somatostatin and neuropeptide Y expressing interneurons. GFAP staining intensity and number of reactive astrocytes markedly increased in lesioned areas of Spry2/4+/− mice as compared with wildtype mice. Taken together, although the seizure threshold is reduced in naive Spry2/4+/− mice, neurodegeneration and GCD is mitigated following KA induced hippocampal lesions, identifying Spry proteins as possible pharmacological targets in brain injuries resulting in neurodegeneration. The present data are consistent with the established functions of the ERK pathway in astrocyte proliferation as well as protection from neuronal cell death and suggest a novel role of Spry proteins in the migration of differentiated neurons. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood

The synthetic progestin, 17α-hydroxyprogesterone caproate, is increasingly used for the prevention of premature birth in at-risk women, despite little understanding of the potential effects on the developing brain. Rodent models suggest that many regions of the developing brain are sensitive to progestins, including the mesocortical dopamine pathway, a neural circuit important for complex cognitive behaviors later in life. Nuclear progesterone receptor is expressed during perinatal development in dopaminergic cells of the ventral tegmental area that project to the medial prefrontal cortex. Progesterone receptor is also expressed in the subplate and in pyramidal cell layers II/III of medial prefrontal cortex during periods of dopaminergic synaptogenesis. In the present study, exposure to 17α-hydroxyprogesterone caproate during development of the mesocortical dopamine pathway in rats altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life, perhaps to a greater extent in males. These studies provide evidence for developmental neurobehavioral effects of a drug in widespread clinical use and highlight the need for a reevaluation of the benefits and potential outcomes of prophylactic progestin administration for the prevention of premature delivery.

The hippocampus participates in the control of locomotion speed

The hippocampus role in sensory-motor integration remains unclear. In these experiments we study its function in the locomotor control. To establish the connection between the hippocampus and the locomotor system, electrical stimulation in the CA1 region was applied and EMG recordings were obtained. We also evaluated the hindlimbs and forelimbs kinematic patterns in rats with a penetrating injury (PI) in the hippocampus as well as in a cortex-injured group (CI), which served as control. After the PI, tamoxifen a selective estrogen receptor modulator (SERM) that has been described as a neuroprotector and antiinflammatory drug, or vehicle was administered. Electrical stimulation in the hippocampus produces muscle contractions in the contralateral triceps, when 6Hz or 8Hz pulse trains were applied. The penetrating injury in the hippocampus reduced the EMG amplitude after the electrical stimulation. At 7DPI (days post-injury) we observed an increase in the strides speed in all four limbs of the non-treated group, decreasing the correlation percentage of the studied joints. After 15DPI the strides speed in the non-treated returned to normal. These changes did not occur in the tamoxifen group nor in cortex-injured group. After 30days, the nontreated group presented a reduction in the number of pyramidal cell layer neurons at the injury site, in comparison to the tam-treated group. The loss of neurons, may cause the interruption of the trisynaptic circuit and changes in the locomotion speed. Tamoxifen preserves the pyramidal neurons after the injury, probably resulting in the strides speed recovery.