Dorsal CA1 Research Articles

Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction.

Na+ /K+ -ATPase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (AHC) including epilepsy. Because the gene is expressed in all neurons, particularly γ-aminobutyric acid (GABA)ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast-spiking interneurons, which have increased firing rates, would be most vulnerable. We performed extracellular recordings, as well as whole-cell patch clamp recordings from pyramidal cells and interneurons, in the CA1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count CA1 pyramidal cells as well as parvalbumin-positive interneurons. In addition, we performed video-electroencephalography (EEG) recordings from the dorsal hippocampal CA1 region. We observed that juvenile knock-in mice carrying the above mutation reproduce the human phenotype of AHC. We then demonstrated in the CA1 region of these mice the following findings as compared to wild type: (1) Increased number of spikes evoked by electrical stimulation of Schaffer collaterals; (2) equalization by bicuculline of the number of spikes induced by Schaffer collateral stimulation; (3) reduced miniature, spontaneous, and evoked inhibitory postsynaptic currents, but no change in excitatory postsynaptic currents; (4) robust action potential frequency adaptation in response to depolarizing current injection in CA1 fast-spiking interneurons; and (5) no change in the number of pyramidal cells, but reduced number of parvalbumin positive interneurons. Our data indicate that, in our genetic model of Atp1α3 mutation, there is increased excitability and marked dysfunction in GABAergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in GABAergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.

A Dorsal Hippocampus-Accumbens Circuit Motif to Guide Appetitive Memory in Space

Retrieving and acting upon memories of food-predicting environments are essential for survival. Pyramidal cells (PYRs) in dorsal CA1 hippocampus (dCA1) of the mammalian brain provide mnemonic representations of space. While dCA1 PYRs cannot directly access motor centers, the brain substrates by which these internal representations guide appetitive behavior are unknown. Here, we uncover a circuit motif embedded in the nucleus accumbens (NAc) that enables the behavioral readout of reward-place memories. By monitoring neuronal ensemble activity in mouse dCA1-NAc pathway, combined with cell-type-selective optogenetic manipulations of dCA1-input-defined postsynaptic neurons, we show that PYRs innervate and engage NAc parvalbumin-expressing fast-spiking interneurons (PV+ FSIs) to influence medium spiny neuron (MSN) firing and thus, NAc output. This motif is specialized for memory-guided appetitive behavior, being dispensable for spatial novelty detection and hedonic motivation. Our findings demonstrate that this PYR-PV+ FSI-MSN circuit motif instantiates a limbic-motor interface for hippocampal representations of space to promote behaviorally-effective appetitive memory.

Hippocampal and amygdalar cell-specific translation is similar soon after stress but diverge over time.

Stress is known to cause contrasting patterns of morphological and physiological plasticity in the hippocampus and amygdala. An obligatory cellular process underlying such neural changes is de novo translation and alterations in protein expression. Yet the nature of the translational response to stress in neurons remains largely unexplored. Even less is known about how glia are affected. Using a click-chemistry-based method to label the de novo proteome in live brain slices, we monitored translation in neurons and astrocytes of the basolateral amygdala (BLA) and dorsal hippocampal area CA3 (dCA3) in rats at different time-points after a single 2-hr exposure to immobilization stress. We observed enhancements in neuronal translation in both brain regions 1 hour after stress. This initial increase persisted in the BLA up to 10days afterwards. In contrast, dCA3 neuronal translation gradually decreased to below control levels 10days later. Translation profiles of dCA3 astrocytes followed timelines similar to neurons, but in BLA astrocytes translation peaked 1day later and remained elevated 10days later. Together our results demonstrate that stress causes an immediate upregulation of protein synthesis in both amygdalar and hippocampal neurons and astrocytes. However, these two areas eventually exhibit opposite temporal profiles of protein expression well after the end of stress. These findings identify new metrics of stress-induced plasticity at the level of cell-type specific proteomic landscape that may provide important insights into the molecular basis of the divergent temporal effects of stress across brain regions and biological scales.

The cognitive nuances of surprising events: exposure to unexpected stimuli elicits firing variations in neurons of the dorsal CA1 hippocampus

The ability to recognize novel situations is among the most fascinating and vital of the brain functions. A hypothesis posits that encoding of novelty is prompted by failures in expectancy, according to computation matching incoming information with stored events. Thus, unexpected changes in context are detected within the hippocampus and transferred to downstream structures, eliciting the arousal of the dopamine system. Nevertheless, the precise locus of detection is a matter of debate. The dorsal CA1 hippocampus (dCA1) appears as an ideal candidate for operating a mismatch computation and discriminating the occurrence of diverse stimuli within the same environment. In this study, we sought to determine dCA1 neuronal firing during the experience of novel stimuli embedded in familiar contexts. We performed population recordings while head-fixed mice navigated virtual environments. Three stimuli were employed, namely a novel pattern of visual cues, an odor, and a reward with enhanced valence. The encounter of unexpected events elicited profound variations in dCA1 that were assessed both as opposite rate directions and altered network connectivity. When experienced in sequence, novel stimuli elicited specific responses that often exhibited cross-sensitization. Short-latency, event-triggered responses were in accordance with the detection of novelty being computed within dCA1. We postulate that firing variations trigger neuronal disinhibition, and constitute a fundamental mechanism in the processing of unexpected events and in learning. Elucidating the mechanisms underlying detection and computation of novelty might help in understanding hippocampal-dependent cognitive dysfunctions associated with neuropathologies and psychiatric conditions.

Dendrites of the dorsal and ventral hippocampal CA1 pyramidal neurons of singly housed female rats exhibit lamina-specific growths and retractions during adolescence that are responsive to pair housing.

Adolescence is accompanied by increased vulnerability to psychiatric illnesses, including anxiety, depression, schizophrenia, and eating disorders. The hippocampus is important for regulating emotional state through its ventral compartment and spatial cognition through its dorsal compartment. Previous animal studies have examined hippocampal development at stages before, after or at single time points during adolescence. However, only one study has investigated morphological changes at multiple time points during adolescence, and no study has yet compared developmental changes of dorsal versus ventral hippocampi. We analyzed the dorsal and ventral hippocampi of rats to determine the developmental trajectory of Golgi-stained hippocampal CA1 neurons by sampling at five time points, ranging from postnatal day (P) 35 (puberty) to 55 (end of adolescence). We show that the dorsal hippocampus undergoes transient dendritic retractions in stratum radiatum (SR), while the ventral hippocampus undergoes transient dendritic growths in SR. During adulthood, stress and hormonal fluctuations have been shown to alter the physiology and morphology of hippocampal neurons, but studies of the impact of these factors upon adolescent hippocampi are scarce. In addition, we show that female-female pair housing from P 36-44 significantly increases branching in the dorsal SR and reduces branching in the ventral SR. Taken together with data on spine density, these results indicate that pyramidal cells in the dorsal and ventral CA1 of female adolescents are remodeled differently following single housing. Social housing during adolescence elicits pathway-specific changes in the hippocampus that may underlie behavioral benefits, including stability of emotion regulation and superior cognition.

Cross state-dependency of learning between tramadol and MK-801 in the mouse dorsal hippocampus: involvement of nitric oxide (NO) signaling pathway.

Tramadol, an atypical μ-opioid receptor agonist, as a psychoactive drug, is frequently abused by human beings. Understanding the neurobiological mechanisms of drug-associated learning and memory formation may help prevent drug addiction and relapse. Previous study revealed that dorsal hippocampus (CA1) plays a crucial role in the retrieval of tramadol-associated memory and that its role depends on the expression of CA1 N-methyl-D-aspartate (NMDA) receptors (Jafari-Sabet et al.Can J Physiol Pharmacol 96:45-50, 2018). To clarify the exact mechanisms involved, the activation of CA1 nitric oxide (NO) signaling pathway by L-arginine (a nitric oxide precursor) on the interaction between tramadol and MK-801 in memory retrieval was examined. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated and a single-trial step-down inhibitory avoidance apparatus was used for the assessment of memory retrieval. Post-training and/or pre-test microinjection of tramadol (0.5 and 1μg/mouse) and/or a non-competitive NMDA receptor antagonist, MK-801 (0.25 and 0.5μg/mouse), induced amnesia which were reversed when the same doses of the drugs were administered 24h later in a pre-test session, suggesting tramadol state-dependent learning (SDL) and MK-801 SDL. The amnesia induced by post-training microinjection of tramadol (1μg/mouse) was reversed by pre-test microinjection of MK-801 (0.25 and 0.5μg/mouse). Pre-test microinjection of MK-801 (0.125 and 0.25μg/mouse) with an ineffective dose of tramadol (0.25μg/mouse) potentiated tramadol SDL. The amnesia induced by post-training microinjection of MK-801 (0.5μg/mouse) was reversed by pre-test microinjection of tramadol (0.5 and 1μg/mouse). Pre-test microinjection of tramadol (0.25 and 0.5μg/mouse) with an ineffective dose of MK-801 (0.125μg/mouse) potentiated MK-801 SDL. Pre-test microinjection of ineffective doses of L-arginine (0.125, 025, and 0.5μg/mouse) improved amnesia induced by the co-administration of tramadol and MK-801. Pre-test microinjection of L-arginine (0.125, 025, and 0.5μg/mouse) could not reverse amnesia induced by post-training microinjection of tramadol while same doses of L-arginine improved MK-801 response on tramadol SDL. The results strongly propose that activation of CA1 NO signaling pathway has a pivotal role in cross SDL among tramadol and MK-801.

Glutamatergic drive along the septo-temporal axis of hippocampus boosts prelimbic oscillations in the neonatal mouse

The long-range coupling within prefrontal-hippocampal networks that account for cognitive performance emerges early in life. The discontinuous hippocampal theta bursts have been proposed to drive the generation of neonatal prefrontal oscillations, yet the cellular substrate of these early interactions is still unresolved. Here, we selectively target optogenetic manipulation of glutamatergic projection neurons in the CA1 area of either dorsal or intermediate/ventral hippocampus at neonatal age to elucidate their contribution to the emergence of prefrontal oscillatory entrainment. We show that despite stronger theta and ripples power in dorsal hippocampus, the prefrontal cortex is mainly coupled with intermediate/ventral hippocampus by phase-locking of neuronal firing via dense direct axonal projections. Theta band-confined activation by light of pyramidal neurons in intermediate/ventral but not dorsal CA1 that were transfected by in utero electroporation with high-efficiency channelrhodopsin boosts prefrontal oscillations. Our data causally elucidate the cellular origin of the long-range coupling in the developing brain.

Dorsal CA1 interneurons contribute to acute stress-induced spatial memory deficits

Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs declarative memory. GABAergic interneurons coordinate neuronal network activity, but their involvement in stress-evoked memory loss remains to be elucidated. Here, we provide evidence that interneurons in area CA1 of the dorsal hippocampus partially modulate acute stress-induced memory deficits. In adult male mice, both acute forced swim stress and restraint stress impaired hippocampus-dependent spatial memory and increased the density of c-fos-positive interneurons in the dorsal CA1. Selective activation of dorsal CA1 interneurons by chemogenetics disrupted memory performance in the spatial object recognition task. In comparison, anxiety-related behavior, spatial working memory and novel object recognition memory remained intact when dorsal CA1 interneurons were overactivated. Moreover, chemogenetic activation of dorsal CA1 interneurons suppressed the activity of adjacent pyramidal neurons, whereas a single exposure to forced swim stress but not restraint stress increased the activity of CA1 pyramidal neurons. However, chemogenetic inhibition of dorsal CA1 interneurons led to spatial memory impairments and failed to attenuate acute stress-induced memory loss. These findings suggest that acute stress may overactivate interneurons in the dorsal CA1, which reduces the activity of pyramidal neurons and in turn disrupts long-term memory.

Ventral Hippocampal CA1 and CA3 Differentially Mediate Learned Approach-Avoidance Conflict Processing

Approach-avoidance conflict arises when an animalencounters a stimulus that is associated simultaneously with positive and negative valences [1]. The effective resolution of approach-avoidance conflict is critical for survival and is believed to go awry in a number of mental disorders, such as anxiety and addiction. An accumulation of evidence from both rodents and humans suggests that the ventral hippocampus (anterior in humans) plays a key role in approach-avoidance conflict processing [2-8], with one influential model proposing that this structure modulates behavioral inhibition in the face of conflicting goals by increasing the influence of negative valences [9]. Very little is known, however, about the contributions of specific hippocampal subregions to this process-an important issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced anavoidance of a conflict cue imbued with both learned positive and learned negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference forthe conflict cue. In contrast, dorsal CA1- andCA3-inactivated rats showed no change in conflictbehavior, and furthermore, additional behavioral tasks confirmed that the observed pattern of approach-avoidance findings could notbe explained by other factors, such as differential alterations in novelty detection or locomotor activity. Our data demonstrate that ventral CA1 and CA3 subserve distinct and opposing roles inapproach-avoidance conflict processing and provide important insight into the functions and circuitry of the ventral hippocampus.

New Hippocampal Circuit Organization Revealed by Viral‐genetic Tracing and Functional Circuit Mapping

The hippocampal formation plays essential roles in learning and memory, and spatial navigation. Although the general anatomy and circuit organization of hippocampal CA1 has been well‐studied, most of our understanding of hippocampal circuits comes from the conventional anatomical tracing studies which lack cell‐type specificity and quantitative measurements of connectional strengths. New advances in virology and molecular genetics complement traditional approaches and are powerful tools for mapping cell‐type‐specific circuit connectivity and function. Using monosynaptic rabies tracing, we recently discovered a non‐canonical but significant set of back‐projections comprised of both excitatory and inhibitory elements from the subiculum to CA1 in the mouse. This discovery suggests previously unconsidered functional roles for direct subicular modulation of hippocampal CA1 circuit activity. In this talk, I will first report our quantitative analysis of canonical‐ and non‐canonical inputs to excitatory neurons in dorsal hippocampal CA1. We find that comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Non‐canonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum‐CA1 input strength systematically increases but the presubiculum‐CA1 input strength decreases along the proximal‐distal axis. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 physiological representations. Further, to test the hypothesis that CA1‐projecting subiculum neurons integrate strong CA1 and local subicular inputs to exert direct feedback regulation of CA1 circuit activity, we map and compare global circuit input and output connections of CA1‐projecting and other excitatory subicular neurons using retrograde monosynaptic rabies tracing and anterograde directed herpes simplex virus (H129 strain) in intact brains, respectively. In conjunction with behavior analysis and genetically targeted neuronal activation and inactivation, in vivo GCaMP6‐based calcium imaging of CA1 neurons in freely moving animals is used to resolve how CA1‐projecting subicular neurons modulate CA1 place cell activity and how they contribute to location dependent learning and memory. Together, these studies provide new insights into this subicular‐CA1 pathway, and advance our understanding of how the subiculum interacts with CA1 to regulate hippocampal circuit activity and learning and memory behaviors.Support or Funding InformationThis research is supported by the National Institutes of Health grant (R01NS078434).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses.

Hippocampus is importantly involved in dopamine-dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta-burst stimulation-induced long-term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral-CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 μM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50-150 μM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 μM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor-mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.

Abstinence to chronic methamphetamine switches connectivity between striatal, hippocampal and sensorimotor regions and increases cerebral blood volume response

Methamphetamine (meth), and other psychostimulants such as cocaine, present a persistent problem for society with chronic users being highly prone to relapse. We show, in a chronic methamphetamine administration model, that discontinuation of drug for more than a week produces much larger changes in overall meth-induced brain connectivity and cerebral blood volume (CBV) response than changes that occur immediately following meth administration. Areas showing the largest changes were hippocampal, limbic striatum and sensorimotor cortical regions as well as brain stem areas including the pedunculopontine tegmentum (PPTg) and pontine nuclei – regions known to be important in mediating reinstatement of drug-taking after abstinence. These changes occur concomitantly with behavioral sensitization and appear to be mediated through increases in dopamine D1 and D3 and decreases in D2 receptor protein and mRNA expression. We further identify a novel region of dorsal caudate/putamen, with a low density of calbindin neurons, that has an opposite hemodynamic response to meth than the rest of the caudate/putamen and accumbens and shows very strong correlation with dorsal CA1 and CA3 hippocampus. This correlation switches following meth abstinence from CA1/CA3 to strong connections with ventral hippocampus (ventral subiculum) and nucleus accumbens. These data provide novel evidence for temporal alterations in brain connectivity where chronic meth can subvert hippocampal – striatal interactions from cognitive control regions to regions that mediate drug reinstatement. Our results also demonstrate that the signs and magnitudes of the induced CBV changes following challenge with meth or a D3-preferring agonist are a complementary read out of the relative changes that occur in D1, D2 and D3 receptors using protein or mRNA levels.

Electrophysiological and Morphological Characterization of Chrna2 Cells in the Subiculum and CA1 of the Hippocampus: An Optogenetic Investigation.

The nicotinic acetylcholine receptor alpha2 subunit (Chrna2) is a specific marker for oriens lacunosum-moleculare (OLM) interneurons in the dorsal CA1 region of the hippocampus. It was recently shown using a Chrna2-cre mice line that OLM interneurons can modulate entorhinal cortex and CA3 inputs and may therefore have an important role in gating, encoding, and recall of memory. In this study, we have used a combination of electrophysiology and optogenetics using Chrna2-cre mice to determine the role of Chrna2 interneurons in the subiculum area, the main output region of the hippocampus. We aimed to assess the similarities between Chrna2 subiculum and CA1 neurons in terms of the expression of interneuron markers, their membrane properties, and their inhibitory input to pyramidal neurons. We found that subiculum and CA1 dorsal Chrna2 cells similarly expressed the marker somatostatin and had comparable membrane and firing properties. The somas of Chrna2 cells in both regions were found in the deepest layer with axons projecting superficially. However, subiculum Chrna2 cells displayed more extensive projections with dendrites which occupied a significantly larger area than in CA1. The post-synaptic responses elicited by Chrna2 cells in pyramidal cells of both regions revealed comparable inhibitory responses elicited by GABAA receptors and, interestingly, GABAB receptor mediated components. This study provides the first in-depth characterization of Chrna2 cells in the subiculum, and suggests that subiculum and CA1 Chrna2 cells are generally similar and may play comparable roles in both sub-regions.

Learning and memory is modulated by cannabidiol when administered during trace fear-conditioning.

Cannabidiol (CBD) is thought to have therapeutic potential for treating psychiatric conditions that affect cognitive aspects of learning and memory, including anxiety and post-traumatic stress disorder (PTSD). Studies have shown that CBD enhances extinction of fear memory when given after conditioning. This led us to hypothesize that CBD, if administered prior to fear conditioning, might modulate cognitive learning and memory processes in additional ways that would further guide its potential use for treating PTSD. Therefore, we designed a study to investigate effects of CBD on fear learning and memory when administered to mice prior to administering a trace fear conditioning protocol which imposes cognitive demands on the learning and memory process. We show that CBD-treated animals had increased levels of freezing during conditioning, enhanced generalized fear, inhibited cue-dependent memory extinction, slightly increased levels of freezing during an auditory-cued memory test, and increased contextual fear memory. Because synaptic plasticity is the fundamental mechanism of learning and memory, we also evaluated the impact of CBD on trace conditioning-dependent dendritic spine plasticity which occurred in the dorsal lateral amygdala and CA1 region of the ventral hippocampus. We showed that CBD mildly enhanced spine densities independent of conditioning, and inhibited conditioning-dependent spine increases in the hippocampi, but not the amygdala of fear conditioned animals. Overall, the memory-modulating effects of a single pre-conditioning dose of CBD, which we show here, demonstrate the need to more fully characterize its basic effects on memory, suggest caution when using it clinically as an anxiolytic, and point to a need for more research into its potential as a therapeutic for treating memory-loss disorders.

Running exercise mitigates the negative consequences of chronic stress on dorsal hippocampal long-term potentiation in male mice.

In the hippocampus, learning and memory are likely mediated by synaptic plasticity, known as long-term potentiation (LTP). While chronic intermittent stress is negatively correlated, and exercise positively correlated to LTP induction, we examined whether exercise could mitigate the negative consequences of stress on LTP when co-occurring with stress. Mice were divided into four groups: sedentary no stress, exercise no stress, exercise with stress, and sedentary with stress. Field electrophysiology performed on brain slices confirmed that stress alone significantly reduced dorsal CA1 hippocampal LTP and exercise alone increased LTP compared to controls. Exercise with stress mice exhibited LTP that was significantly greater than mice undergoing stress alone but were not different from sedentary no stress mice. An ELISA illustrated increased corticosterone in stressed mice compared to no stress mice. In addition, a radial arm maze was used to examine behavioral changes in memory during 6 weeks of stress and/or exercise. Exercised mice groups made fewer errors in week 2. RT-qPCR was used to examine the mRNA expression of components in the stress and exercise pathways in the four groups. Significant changes in the expression of the following targets were detected: BDNF, TrkB, glucocorticoid, mineralocorticoid, and dopamine 5 receptors. Collectively, exercise can mitigate some of the negative impact stress has on hippocampal function when both occur concurrently.

A role for CA3 in social recognition memory

Social recognition memory is crucial for survival across species, underlying the need to correctly identify conspecifics, mates and potential enemies. In humans the hippocampus is engaged in social and episodic memory, however the circuit mechanisms of social memory in rodent models has only recently come under scrutiny. Work in mice has established that the dorsal CA2 and ventral CA1 regions play critical roles, however a more comprehensive comparative analyses of the circuits and mechanisms required has not been reported. Here we employ conditional genetics to examine the differential contributions of the hippocampal subfields to social memory. We find that the deletion of NMDA receptor subunit 1 gene (NR1), which abolishes NMDA receptor synaptic plasticity, in CA3 pyramidal cells led to deficits in social memory; however, mice lacking the same gene in DG granule cells performed indistinguishable from controls. Further, we use conditional pharmacogenetic inhibition to demonstrate that activity in ventral, but not dorsal, CA3 is necessary for the encoding of a social memory. These findings demonstrated CA3 pyramidal cell plasticity and transmission contribute to the encoding of social stimuli and help further identify the distinct circuits underlying the role of the hippocampus in social memory.

Spatial processing: An 'other' kind of place cell.

'Social place cells' of the dorsal hippocampal CA1 region in bats and in rats encode the position of an observed conspecific.

Anxiety Cells in a Hippocampal-Hypothalamic Circuit

The hippocampus is traditionally thought to transmit contextual information to limbic structures where it acquires valence. Using freely moving calcium imaging and optogenetics, we show that while the dorsal CA1 subregion of the hippocampus is enriched in place cells, ventral CA1 (vCA1) is enriched in anxiety cells that are activated by anxiogenic environments and required for avoidance behavior. Imaging cells defined by their projection target revealed that anxiety cells were enriched in the vCA1 population projecting to the lateral hypothalamic area (LHA) but not to the basal amygdala (BA). Consistent with this selectivity, optogenetic activation of vCA1 terminals in LHA but not BA increased anxiety and avoidance, while activation of terminals in BA but not LHA impaired contextual fear memory. Thus, the hippocampus encodes not only neutral but also valence-related contextual information, and the vCA1-LHA pathway is a direct route by which the hippocampus can rapidly influence innate anxiety behavior.

Blockade of dopamine D2 receptors disrupts intrahippocampal connectivity and enhances pain-related working memory deficits in neuropathic pain rats.

Dopamine (DA) is thought to be important to local hippocampal networks integrity during spatial working memory (sWM) processing. Chronic pain may contribute to deficient dopaminergic signalling, which may in turn affect cognition. However, the neural mechanisms that determine this impairment are poorly understood. Here, we evaluated whether the sWM impairment characteristic of animal models of chronic pain is dependent on DA D2 receptor (D2r) activity. To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 field (dvCA1) of rats and recorded the neuronal activity during a classical delayed food-reinforced T-maze sWM task. Within-subject behavioural performance and patterns of dorsoventral neural activity were assessed before and after the onset of persistent neuropathic pain using the spared nerve injury (SNI) model. Our results show that the peripheral nerve lesion caused a disruption in sWM and hippocampus spike activity and that disruption was maximized by the systemic administration of the D2r antagonist raclopride. These deficits are strictly correlated with a selective disruption of hippocampal theta-oscillations. Particularly, we found a significant decrease in intrahippocampal CA1 field connectivity level. Together, these results suggest that disruption of the dopaminergic balance in the intrahippocampal networks may be important for the development of cognitive deficits experienced during painful conditions. This study provides new insights into the role of D2r in the manifestation of pain-related sWM deficits. Our findings support that selective blockade of D2r produces a significant decrease in intrahippocampal connectivity mediated by theta-oscillations, and amplifies pain-related sWM deficits. These results suggest that further characterization of intrahippocampal dopaminergic modulation may be clinically relevant for the understanding of cognitive impairments that accompanies nociceptive stressful conditions.

Spatial representations of self and other in the hippocampus.

An animal's awareness of its location in space depends on the activity of place cells in the hippocampus. How the brain encodes the spatial position of others has not yet been identified. We investigated neuronal representations of other animals' locations in the dorsal CA1 region of the hippocampus with an observational T-maze task in which one rat was required to observe another rat's trajectory to successfully retrieve a reward. Information reflecting the spatial location of both the self and the other was jointly and discretely encoded by CA1 pyramidal cells in the observer rat. A subset of CA1 pyramidal cells exhibited spatial receptive fields that were identical for the self and the other. These findings demonstrate that hippocampal spatial representations include dimensions for both self and nonself.