Dorsal CA1 Research Articles

Epilepsy-Induced Reduction in HCN Channel Expression Contributes to an Increased Excitability in Dorsal, But Not Ventral, Hippocampal CA1 Neurons.

CA1 neurons in epileptic animals are vulnerable to selective changes in ion channel expression, called acquired channelopathies, which can increase the excitability of a neuron. Under normal conditions there is a gradient of ion channel expression and intrinsic excitability along the longitudinal, dorsoventral axis of hippocampal area CA1 of the rodent. Many of these channels, including M-channels, GIRK channels and HCN channels, all have dorsoventral expression gradients that might be altered in rodent models of epilepsy. Here, we show that the excitability of dorsal, but not ventral CA1 neurons, had an increased firing rate, reduced interspike interval (ISI) and increased input resistance in a status epilepticus (SE) model of temporal lobe epilepsy (TLE). As a result, the excitability of CA1 neurons became uniform across the dorsoventral axis of the rat hippocampus post-SE. Using current clamp recordings with pharmacology and immunohistochemistry, we demonstrate that the expression of HCN channels was downregulated in the dorsal CA1 region post-SE, while the expression of M and GIRK channels were unchanged. We did not find this acquired channelopathy in ventral CA1 neurons post-SE. Our results suggest that the excitability of dorsal CA1 neurons post-SE increase to resemble the intrinsic properties of ventral CA1 neurons, which likely makes the hippocampal circuit more permissible to seizures, and contributes to the cognitive impairments associated with chronic epilepsy.

Learning Promotes Subfield-Specific Synaptic Diversity in Hippocampal CA1 Neurons

The hippocampus is functionally heterogeneous between the dorsal and ventral subfields with left–right asymmetry. To determine the possible location of contextual memory, we performed an inhibitory avoidance task to analyze synaptic plasticity using slice patch-clamp technique. The training bilaterally increased the AMPA/NMDA ratio at dorsal CA3–CA1 synapses, whereas the training did not affect the ratio at ventral CA3–CA1 synapses regardless of the hemisphere. Moreover, sequential recording of miniature excitatory postsynaptic currents and miniature inhibitory postsynaptic currents from the same CA1 neuron clearly showed learning-induced synaptic plasticity. In dorsal CA1 neurons, the training dramatically strengthened both excitatory and inhibitory postsynaptic responses in both hemispheres, whereas the training did not promote the plasticity in either hemisphere in ventral CA1 neurons. Nonstationary fluctuation analysis further revealed that the training bilaterally increased the number of AMPA or GABAA receptor channels at dorsal CA1 synapses, but not at ventral CA1 synapses, suggesting functional heterogeneity of learning-induced receptor mobility. Finally, the performance clearly impaired by the bilateral microinjection of plasticity blockers in dorsal, but not ventral CA1 subfields, suggesting a crucial role for contextual learning. The quantification of synaptic diversity in specified CA1 subfields may help us to diagnose and evaluate cognitive disorders at the information level.

Restraint stress exacerbates cell degeneration induced by acute binge ethanol in the adolescent, but not in the adult or middle-aged, brain.

Restraint stress (RS) induces neurotoxicity in the hippocampus, yet most of the studies have employed protracted RS (i.e., ≈ 21 days). Binge ethanol can induce brain toxicity, an effect affected by age. It could be postulated that RS may facilitate ethanol-induced neurotoxicity, perhaps to a greater extent in adolescent vs. older subjects. We analyzed whether adolescent, adult or middle-aged male rats exposed to five episodes of RS followed, 72h later, by binge ethanol (i.e., two administrations of 2.5 g/kg ethanol) exhibited hippocampal neurotoxicity. Adolescents, but not adult or middle-aged rats, exhibited sensitivity to the neurotoxic effects of ethanol at dorsal CA2, ventral CA3 and ventral DG, and a neurotoxic effect of stress at dorsal CA1. Moreover, the combination of ethanol and stress exerted a synergistic effect upon cell degeneration at ventral CA1 and CA2, which was restricted to adolescents. Ethanol also increased cell degeneration, irrespective of age or stress, in dorsal CA3 and in dorsal DG; and ethanol and stress had, across all ages, a synergistic effect upon cell degeneration at the dorsal CA1. The greater neurotoxic response of adolescents to ethanol, stress, or ethanol+stress can put them at risk for the development of alcohol problems.

Cross state-dependency of learning between 5-HT1A and/or 5-HT7 receptor agonists and muscimol in the mouse dorsal hippocampus.

Dysfunction of the serotonergic and GABAergic systems in cognitive disorders has been revealed. Understanding the neurobiological mechanisms of drug-associated learning and memory formation may help treatment of cognitive disorders. The aim of the present study was to investigate: 1) 8-OH-DPAT (5-HT1A agonist), AS19 (5-HT7 agonist) and muscimol (GABA-A agonist) on memory retrieval and state of memory, 2) cross state-dependent learning between 8-OH-DPAT and/or AS19 and muscimol. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended sites of injection. A single-trial step-down inhibitory avoidance task was used for the evaluation of memory retrieval and state of memory. Post-training and/or pre-test 8-OH-DPAT, AS19 and muscimol induced amnesia. Pre-test microinjection of the same doses of 8-OH-DPAT, AS19 and muscimol reversed the post-training 8-OH-DPAT-, AS19- and muscimol-induced amnesia, respectively. This event has been named state-dependent learning (SDL). The amnesia induced by 8-OH-DPAT was reversed by muscimol and induced 8-OH-DPAT SDL. The amnesia induced by muscimol was reversed by 8-OH-DPAT and induced muscimol SDL. The amnesia induced by AS19 was reversed by muscimol and induced AS19 SDL. The amnesia induced by muscimol was reversed by AS19 and induced muscimol SDL. Pre-test administration of a selective GABA-A receptor antagonist, bicuculline, 5 min before muscimol, 8-OH-DPAT and AS19 dose-dependently inhibited muscimol-, 8-OH-DPAT- and AS19-induced SDL, respectively. The results strongly revealed a cross SDL among 8-OH-DPAT and/or AS19 and muscimol in the dorsal hippocampal CA1 regions.

Interaction of Taste and Place Coding in the Hippocampus.

An animal's survival depends on finding food and the memory of food and contexts are often linked. Given that the hippocampus is required for spatial and contextual memory, it is reasonable to expect related coding of space and food stimuli in hippocampal neurons. However, relatively little is known about how the hippocampus responds to tastes, the most central sensory property of food. In this study, we examined the taste-evoked responses and spatial firing properties of single units in the dorsal CA1 hippocampal region as male rats received a battery of taste stimuli differing in both chemical composition and palatability within a specific spatial context. We identified a subset of hippocampal neurons that responded to tastes, some of which were place cells. These taste and place responses had a distinct interaction: taste-responsive cells tended to have less spatially specific firing fields and place cells only responded to tastes delivered inside their place field. Like neurons in the amygdala and lateral hypothalamus, hippocampal neurons discriminated between tastes predominantly on the basis of palatability, with taste selectivity emerging concurrently with palatability-relatedness; these responses did not reflect movement or arousal. However, hippocampal taste responses emerged several hundred milliseconds later than responses in other parts of the taste system, suggesting that the hippocampus does not influence real-time taste decisions, instead associating the hedonic value of tastes with a particular context. This incorporation of taste responses into existing hippocampal maps could be one way that animals use past experience to locate food sources.SIGNIFICANCE STATEMENT Finding food is essential for animals' survival and taste and context memory are often linked. Although hippocampal responses to space and contexts have been well characterized, little is known about how the hippocampus responds to tastes. Here, we identified a subset of hippocampal neurons that discriminated between tastes based on palatability. Cells with stronger taste responses typically had weaker spatial responses and taste responses were confined to place cells' firing fields. Hippocampal taste responses emerged later than in other parts of the taste system, suggesting that the hippocampus does not influence taste decisions, but rather associates the hedonic value of tastes consumed within a particular context. This could be one way that animals use past experience to locate food sources.

A Hippocampus-Accumbens Tripartite Neuronal Motif Guides Appetitive Memory in Space

SummaryRetrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior.

Muscarinic activity in hippocampus and entorhinal cortex is crucial for spatial and fear memory retrieval.

Hippocampus and entorhinal cortex are key players of learning and memory. Despite their established role in memory processes, the contribution of muscarinic receptor activity in these brain regions during memory retrieval remains elusive. This study was aimed to assess the role of hippocampal CA1 and medial entorhinal cortex muscarinic receptors in memory retrieval. Mice were implanted with bilateral cannulas in the hippocampus CA1 and medial entorhinal cortex. After recovery they were trained for Morris water maze test, novel object recognition test and contextual fear conditioning. Scopolamine was infused 10 min prior to retrieval test. Pre-test scopolamine infusion in hippocampal CA1 and medial entorhinal cortex significantly reduced overall exploration of objects (p<0.001). Similarly, pre-retrieval inactivation dorsal hippocampal CA1 and medial entorhinal cortex muscarinic activity caused significant impairment of spatial and fear memories retrieval (p<0.05). These findings showed vital role of muscarinic activity in retrieving hippocampal and entorhinal cortex dependent memories and suggest a possible target for treating retrograde amnesia.

D-type potassium channels normalize action potential firing between dorsal and ventral CA1 neurons of the mouse hippocampus.

Specific memory processes and neurological disorders can be ascribed to different dorsoventral regions of the hippocampus. Recently, differences in the anatomical and physiological properties between dorsal and ventral hippocampal CA1 neurons were described for both the rat and mouse hippocampus and have greatly contributed to our understanding of these processes. While differences in the subthreshold properties were similar between rat and mouse neurons, differences in action potential output between dorsal and ventral neurons were strikingly less divergent in mouse compared with rat CA1 neurons. Here, we investigate the mechanism underlying the lack of difference in action potential firing between dorsal and ventral CA1 pyramidal neurons in mouse hippocampus. Consistent with rat, we found that ventral CA1 neurons had a more depolarized resting membrane potential and higher input resistance than dorsal CA1 neurons in the mouse hippocampus. Despite these differences, action potential output in response to current injection was not significantly different. We found that ventral neurons have a more depolarized action potential threshold compared with dorsal neurons and that threshold in ventral neurons was more sensitive to block of KV1 channels compared with dorsal neurons. Outside-out voltage-clamp recordings found that slowly inactivating K+ currents were larger in ventral CA1 neurons. These results suggest that, despite differences in subthreshold properties between dorsal and ventral CA1 neurons, action potential output is normalized by the differential functional expression of D-type K+ channels. NEW & NOTEWORTHY Understanding differences in neurons within a brain region is integral in the reliable interpretation of comparative studies. Our findings identify a novel mechanism by which D-type potassium channels normalize action potential firing between dorsal and ventral CA1 neurons of mouse hippocampus despite differences in subthreshold intrinsic properties. Action potential threshold in ventral neurons is influenced by a greater functional expression of D-type potassium channels resulting in a depolarized action potential threshold compared with dorsal hippocampus.

Behavioral, cognitive and histological changes following neonatal anoxia: Male and female rats’ differences at adolescent age

Neonatal anoxia induces long-term brain injury that may underlie neurobehavioral deficits at adolescence. Neonatal anoxia, induced by exposure of 30-hour old pups to 100% nitrogen, represents a non-invasive and global stimulus, which simulates clinical conditions of human pre-term babies (around 6 gestational months). Previous studies showed that neonatal anoxia induced impairments of spatial memory and altered anxiety-like behaviors in male rats tested at adult age. This study evaluated if neonatal anoxia induces similar behavioral effects in female rats, as compared to males, by testing the animals at adolescence, and also searched for possible cell losses in hippocampal subfields. Results in the Elevated Plus Maze test showed that anoxic females spent proportionally more time within the open arms as compared to anoxic males, suggesting a less anxious-like behavior. In the Morris Water Maze Test, latencies and path lengths of the anoxic subjects were longer as compared to control subjects, thus indicating that anoxia disrupted the cognitive functions required for spatial mapping. In addition, results showed that anoxia-induced disruption was greater in male rats as compared to female rats. Stereological analysis revealed that anoxic male rats exhibited significant cell losses in the dorsal hippocampus dentate gyrus and CA1 subfields, but not in CA3-2 subfield. Similar results were observed in the ventral hippocampus, but now with cell loss in the male CA3-2 subfield. There were also significant cell loss differences of anoxic male rats as compared to anoxic female rats. In conclusion, neonatal anoxia induces deleterious and long lasting behavioral and cognitive disruptions, and these effects were stronger in male rats as compared to female rats. These changes are congruent with the pattern of cell losses observed in hippocampal subfields. Together, these results emphasize the relevance of scientific research, aiming at clinical strategies and treatments, consider the sex differential patterns of response to neonatal injury.

Death-associated Protein Kinase 1 Impairs the Hippocampo-prefrontal Cortical Circuit and Mediates Post-stroke Depression

Post-stroke depression (PSD) is a common and complex post-stroke neuropsychiatric disorder, which not only delays functional recovery but also increases mortality, and which currently lacks effective drug therapy. The pathogenesis of PSD is associated with impairment of the subcortical neural circuits and alterations of synaptic plasticity and neurotransmitters, but the exact mechanisms of PSD remain unknown. Our previous work indicates that the death-associated protein kinase 1 (DAPK1) mediates neuronal death after stroke. Genetic deletion of DAPK1 gene or blocking DAPK1 signal in the PSD mouse model can not only alleviate cerebral ischemic injury but also relieve PSD-like behaviors. Our previous work has also demonstrated the following results. First, the neural circuit of dorsal CA1 (dCA1) to medial prefrontal cortex (mPFC) (dCA1-mPFC) is selectively impaired after stroke. Second, the DAPK1 signal is involved in the impairment of dCA1-mPFC neural circuit after stroke. Third, genetic deletion of the DAPK1 gene or blocking of the DAPK1 signal alleviates the injury of dCA1-mPFC neural circuit after stroke and improves PSD-like behaviors. In conclusion, we hypothesize that activated DAPK1 signal after stroke induces apoptosis in the hippocampal dCA1 neurons, leading to loss of the dCA1-mPFC glutamatergic projections, synaptic injury, decrease of glutamate release, inhibition of mPFC neurons, and finally onset of PSD. We hope to further replenish the mechanisms of PSD and provide new insights for PSD treatment.

Hippocampal Place Fields Maintain a Coherent and Flexible Map across Long Timescales

To provide a substrate for remembering where in space events have occurred, place cells must reliably encode the same positions across long timescales. However, in many cases, place cells exhibit instability by randomly reorganizing their place fields between experiences, challenging this premise. Recent evidence suggests that, in some cases, instability could also arise from coherent rotations of place fields, as well as from random reorganization. To investigate this possibility, we performed invivo calcium imaging in dorsal hippocampal region CA1 of freely moving mice while they explored two arenas with different geometry and visual cues across 8days. The two arenas were rotated randomly between sessions and then connected, allowing us to probe how cue rotations, the integration of new information about the environment, and the passage of time concurrently influenced the spatial coherence of place fields. We found that spatially coherent rotations of place-field maps in the same arena predominated, persisting up to 6days later, and that they frequently rotated in a manner that did not match that of the arena rotation. Furthermore, place-field maps were flexible, as mice frequently employed asimilar, coherent configuration of place fields to represent each arena despite their differing geometry and eventual connection. These results highlight theability of the hippocampus to retain consistent relationships between cells across long timescales and suggest that, in many cases, apparent instability might result from a coherent rotation of place fields.

Cortico-hippocampal GluN2B is essential for efficient visual-spatial discrimination learning in a touchscreen paradigm

Discrimination of similar spatial locations, an important feature of episodic memory, has traditionally been measured via delayed nonmatching-to-location tasks. Recently, we and others have demonstrated that touchscreen-based Trial Unique Nonmatching-to-Location (TUNL) tasks are sensitive to lesions of the dorsal hippocampus in the mouse. Previously we have shown that loss of the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor in the dorsal CA1 and throughout the cortex impairs hippocampal-dependent water maze and fear conditioning paradigms. We investigated whether loss of GluN2B would alter performance of visual-spatial discrimination learning in a delay- or separation-dependent manner. GluN2B null mutants displayed initial impairments in accuracy on the easiest training variant of TUNL that were overcome with training. Loss of GluN2B also impaired performance on a problem series where delay and separation were systematically varied. We also observed a training-dependent effect on performance. Mutant mice that received extensive training performed similar to control mice when challenged on a variable delay and variable separation problem, while those that received minimal training were impaired across all delays and separations. Together, these data demonstrate that GluN2B in the dorsal CA1 and cortex are essential for efficient visual-spatial discrimination learning on the TUNL task. Further, training effects on performance in mutant mice suggest that alterations in synaptic plasticity after GluN2B loss may underlie intra- versus inter-session learning.

Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post-synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals.

Episodic-like memory impairment induced by sub-anaesthetic doses of ketamine

Episodic-like memory refers to integration of where and when a certain event (what) happened. The glutamatergic neurotransmission, particularly AMPA and NMDA receptors, in the dorsal hippocampus mediates episodic recall. Ketamine is a non-competitive NMDA antagonist with effect on cognitive performance and plasticity. The goal of this study was to evaluate the acute action of ketamine on behavioural and neurochemical aspects of episodic-like memory (WWWhen/ELM task) through immediate-early gene expression (IEG), c-Fos, in the dorsal hippocampus. Animals received saline 0.9% or ketamine at 8 mg/kg or 15 mg/kg (i.p.) immediately after the second sample. Our data indicate that untreated and saline rats integrate the three elements of episodic-like memory. Conversely, animals treated with ketamine showed impairment of ELM formation. In addition, the highest dose of ketamine increased c-Fos expression in dorsal CA1 subregion when compared to saline rats. Our results indicate that the antagonism of NMDA concurrently impair ELM formation of all three aspects of ELM and increase neuronal activation in dorsal CA1.

A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics

Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory.

PSD-95-nNOS Coupling Regulates Contextual Fear Extinction in the Dorsal CA3

Fear extinction depends on N-methyl-D-aspartate glutamate receptors (NMDARs) and brain-derived neurotrophic factor (BDNF) activation in the limbic system. However, postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) coupling, the downstream signaling of NMDARs activation, obstructs the BDNF signaling transduction. Thus, we wondered distinct roles of NMDAR activation and PSD-95-nNOS coupling on fear extinction. To explore the mechanisms, we detected protein-protein interaction using coimmunoprecipitation and measured protein expression by western blot. Contextual fear extinction induced a shift from PSD-95-nNOS to PSD-95-TrkB association in the dorsal hippocampus and c-Fos expression in the dorsal CA3. Disrupting PSD-95-nNOS coupling in the dorsal CA3 up-regulated phosphorylation of extracellular signal-regulates kinase (ERK) and BDNF, enhanced the association of BDNF-TrkB signaling with PSD-95, and promoted contextual fear extinction. Conversely, blocking NMDARs in the dorsal CA3 down-regulated BDNF expression and hindered contextual fear extinction. NMDARs activation and PSD-95-nNOS coupling play different roles in modulating contextual fear extinction in the hippocampus. Because inhibitors of PSD-95-nNOS interaction produce antidepressant and anxiolytic effect without NMDAR-induced side effects, PSD-95-nNOS could be a valuable target for PTSD treatment.

Long-lasting, reversible and non-neurotoxic inactivation of hippocampus activity induced by neosaxitoxin

BackgroundNeosaxitoxin (NeoSTX) and related paralytics shellfish toxins has been successfully used as local anesthetic and muscle relaxants to treat a variety of ailments. The primary mechanism of action of these toxins occurs by blocking voltage-gated sodium channels with compounds such as TTX, lidocaine, or derivatives. However, most of these non-classical sodium channel blockers act with a reduced time effect as well as ensuing neurotoxicity. New methodIn this report, we show that the use of local NeoSTX injections inactivates the hippocampal neuronal activity reversibly with a by long-term dynamics, without neuronal damage. ResultsA single 10 ng/μl injection of NeoSTX in the dorsal CA1 region abolished for up to 48 h memory capacities and neuronal activity measured by the neuronal marker c-fos. After 72 h of toxin injection, the animals fully recover their memory capacities and hippocampal neuronal activity. The histological inspection of NeoSTX injected brain regions revealed no damage to the tissue or reactive gliosis, similar to vehicle injection. Acute electrophysiological recording in vivo shows, also, minimal spreading of the NeoSTX in the cerebral tissue. Comparison with existing methodsIntracerebral NeoSTX injection showed longer effects than other voltage sodium channel blocker, with minimal spreading and no neuronal damage. ConclusionNeoSTX is a new useful tool that reversibly inactivates different brains region for a long time, with minimal diffusion and without neuronal damage. Moreover, NeoSTX can be used as a valuable sodium channel blocker for many studies in vivo and with potential therapeutic uses.

Nucleus reuniens of the thalamus controls fear memory intensity, specificity and long-term maintenance during consolidation.

The thalamic nucleus reuniens (NR) has been shown to support bidirectional medial prefrontal cortex-hippocampus communication and synchronization relevant for cognitive processing. Using non-selective or prolonged inactivation of the NR, previous studies reported its activity positively modulates aversive memory consolidation. Here we examined the NR's role in consolidating contextual fear memories with varied strength, at both recent and more remote time points, using muscimol-induced temporary inactivation in rats. Results indicate the NR negatively modulates fear memory intensity, specificity, and long-term maintenance. The more intense, generalized, and enduring fear memory induced by NR inactivation during consolidation was less prone to behavioral suppression by extinction or reconsolidation disruption induced by clonidine, an alpha-2 adrenergic receptor agonist. Lastly, we used immunohistochemistry for Arc protein, which is involved in synaptic modifications underlying memory consolidation, to investigate whether treatment condition and/or conditioning status could change its levels not only in the NR, but also in the hippocampus (dorsal and ventral CA1 subregions) and the medial prefrontal cortex (anterior cingulate, prelimbic and infralimbic subregions). Results indicate a significant imbalance in the number of Arc-expressing neurons in the brain areas investigated in muscimol fear conditioned animals when compared with controls. Collectively, present results provide convergent evidence for the NR's role as a hub regulating quantitative and qualitative aspects of a contextual fear memory during its consolidation that seem to influence the subsequent susceptibility to experimental interventions aiming at attenuating its expression. They also indicate the selectivity and duration of a given inactivation approach may influence its outcomes.

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history

Menopause is associated with cognitive decline, and hormone therapies (HTs) may improve cognition depending on type and timing of HTs. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin 6 months later, and all rats were trained in the Morris water maze. Premarin improved early spatial learning and memory in nulliparous rats but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor α and the CXC chemokine ligand 1 (CXCL1) in trained nulliparous, but not primiparous, rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.

Modulation of Kalirin-7 expression by hippocampal CA1 5-HT1B receptors in spatial memory consolidation

Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 μg/μL) or agonist CP93129 (25 μg/μL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation.