Hippocampus

We recently reported that rats performed better at a task distance of 2 m than at 0 m in a T-maze delayed alternation paradigm using a movable home cage in the longer-delay condition (Takita & Ichitani, 2026). We simultaneously recorded local field potentials from the bilateral prefrontal cortex, intermediate hippocampus, and ventral hippocampus. Across task epochs, coherence and two cross-frequency measures (phase-locking value and modulation index [MI]) revealed differences between correct and error trials in prefrontal interactions with hippocampal subregions. Among these measures, only MI was affected by task distance during the pre-task delay epoch. MI was highest in 2-m error trials and lowest in correct trials. In 0-m error trials, MI transiently increased during arm entry to levels comparable to those in 2-m error trials before declining toward the levels observed in correct trials during the later post-task delay. These MI dynamics appeared to be consistent with distance-dependent differences in behavioral performance. In addition, normalized Correct-Error Indices calculated for each electrophysiological measure revealed differential contributions of prefrontal coupling with the intermediate and ventral hippocampus across task distances. These findings suggest the existence of distinct near and far working memory states underlying distance-dependent behavioral differences, with distinct yet complementary contributions of the intermediate and ventral hippocampus to prefrontal interactions.

Spatial navigation requires animals to integrate current environmental information with previously acquired spatial memories. The locus coeruleus provides neuromodulatory input to the hippocampus, but whether this pathway facilitates spatial learning in general or preferentially supports the updating of established representations remains unclear. Here, we selectively activated LC projections to the dorsal hippocampus while mice performed object-location recognition and an appetitive radial-maze task involving initial spatial learning followed by reversal. LC-hippocampal activation enhanced object-location memory and improved reversal learning, reducing total and working-memory errors, but did not affect initial spatial reference acquisition or retention. To characterize navigation beyond classical performance measures, we developed a graph-based analysis comparing each observed trajectory with paths generated from random, regular, small-world and heuristic goal-directed network models. Radial-maze trajectories contained a structured mixture of goal-directed-like and regular or serial-like patterns that evolved across learning. In addition, agreement with the goal-directed model was associated with fewer errors and greater proximity to the rewarded arm. Together, these findings indicate that LC inputs to the hippocampus preferentially facilitate spatial memory updating rather than uniformly enhancing spatial learning, and introduce a complementary framework for quantifying the organization of radial-maze trajectories.

The GABAA positive allosteric modulator diazepam is taken systemically by millions of people daily. GABAA signaling is essential for hippocampal circuit function, but the effects of systemic diazepam on hippocampal information processing during behavior has not been studied. To answer this question, large neural ensembles were recorded from rats running a linear track under systemic diazepam administration. A cross-correlation of spiking activity revealed significantly increased inhibition from interneurons, aligned with the timescale of GABAA, suggesting a direct effect on local circuits. Local field potentials (LFP) showed an increase in theta and lo-gamma (30-50 Hz) power but a decrease in hi-gamma (80-120 Hz) power. We also found decreased amplitude and rate of sharp wave ripple (SWR) events and a reduction of firing rate and proportion of cells recruited to the SWRs. An autocorrelation of single-cell spike trains revealed a decrease and shift from shorter to longer timescales, aligning differently with theta frequencies. Phase coupling measurements showed decreased cellular coupling to theta and increased coupling to lo-gamma and hi-gamma. Finally, entropy of decoding along the track was increased, suggesting less precise spatial representations under diazepam. These changes suggest mechanisms that would likely disrupt hippocampal memory storage and consolidation processes under systemic diazepam.

Automated segmentation has made hippocampal subfield volumes a routine measurement, and studies now report which subfield relates to an outcome rather than whether the hippocampus does. Those reports do not agree with one another, and the standard explanation is insufficient statistical power. We argue that a second limit operates independently of sample size. Using 638 participants from a population-derived adult lifespan cohort, we first show that no individual subfield contributes to a general cognitive factor beyond a single global size component: no coefficient interval excludes zero, the local block carries half a percent of outcome variance, and no model improves out-of-sample prediction over the global factor alone. Because an observed null cannot distinguish an absent effect from an effect the design cannot locate, we then planted effects of known location and size in the measured design and in a whitened copy of it that preserves sample size, dimensionality and effect size while removing only the correlation between subfields. The arms were paired down to the noise vector. Collinearity did not place recovery out of reach; it multiplied the required sample size by a factor of roughly two to three, and the penalty widened as cohorts grew. At the effect sizes this literature reports, neither design reached an adequate recovery rate at any sample size, and coarsening the parcellation rescued neither. The choice of estimator moved recovery further than collinearity did. We provide a calibration surface on which a planned design can be located before data collection.

An environment can be interpreted in multiple ways, with implications for behaviour and neural representations and for revision in these when circumstances change. Using two-photon calcium imaging in mouse CA1 during navigation under structured reward-location uncertainty, we found correlations between variability in anticipatory behaviour and the organization of place fields with respect to position and reward. Greater spatial anticipation was associated with enhanced reward-centred coding and increased generalisability of reward-aligned representations.

Encoding-related pupil responses predict later memory performance, but the neural mechanisms linking these autonomic dynamics to memory formation remain unclear. This study examined whether pupil responses during encoding track activity in the brains memory network and whether they reflect functional interactions between memory-related regions and neural systems involved in pupil control. Participants performed an incidental encoding task involving object stimuli while undergoing simultaneous fMRI and pupillometry; recognition memory was subsequently assessed outside the scanner. Greater pupil constriction during encoding predicted both the strength and quality of later memory. These pupil dynamics correlated with activity in memory-related brain regions, notably the hippocampus and the parahippocampal cortex. Connectivity analyses indicated that encoding-related pupil responses were supported by functional interactions between the hippocampus and the midbrain Edinger-Westphal nucleus, the striatum, and the orbitofrontal cortex. The findings suggest that interactions between memory-related regions and parasympathetic pupil-control systems may modulate encoding efficiency. Together, the results identify encoding-related pupil constriction as a non-invasive marker of memory-network engagement and suggest a hippocampal-midbrain pathway through which autonomic pupil dynamics are coupled with successful memory formation.

In-vivo examination of neurites to understand microstructural properties of white matter tissue utilizing neurite orientation dispersion and density imaging (NODDI) has shown sensitivity to healthy aging as well as disease biomarkers and status. Neurite density index (NDI), which is a proxy for the amount of neurites, in white matter tissue typically decreases with age. However, orientation dispersion index (ODI), which is a proxy for neurite dispersion or fanning, has been mixed with studies finding both increases and decreases with age. Furthermore, white matter tracts are not uniform and hold its own unique spatial pattern or gradient in microstructural properties. In addition to the spatial pattern of the microstructural property, age-related effects have also shown spatial patterns with stronger age effects in the medial, anterior, and dorsal portions of white matter tissue. However, spatial gradients along cardinal axes within an individual's tract have yet to be examined with age in an adult lifespan sample. The current aim of the study was to examine whether average and spatial gradients of neurite microstructural properties within tracts related to the cortico-striato-pallido-thalamic (CSPT) loop were age-sensitive. An adult lifespan sample aged 20-90 years old was recruited from the Dallas-Fort Worth metroplex (N = 104, 62% females) as part of the Dallas Area Longitudinal Lifespan Area Study (DALLAS). Participants completed an MRI session that included a structural T1-weighted image as well as multi-shell diffusion weighted imaging (MS-DWI). MS-DWI were preprocessed and tracts of interest related to the CSPT loop were obtained using probabilistic tractography. For most tracts, a significant inverted-U association with age was found for both average NDI and ODI. Most tracts revealed a reliable spatial gradient of NDI and ODI in the medial-to-lateral, posterior-to-anterior, and ventral-to-dorsal direction. Tracts related to CSPT loop were age-sensitive such that the spatial gradient was becoming more homogenous with age. This loss of spatial gradients with age is analogous to network-level dedifferentiation observed in BOLD functional connectivity. These findings highlight that age effects in a fundamental circuit for both basic and higher-order function is significantly age sensitive and while organized into spatial gradients, these gradients are also vulnerable to aging.

Stress-related experiences alter glutamatergic signaling and neuronal excitability, but the mechanisms that couple experience to dentate granule cell function remain incompletely understood. Here, we examined how protein kinase N1a (PKN1a), a protein kinase C-like serine/threonine kinase, and repeated swim exposure regulate mouse hippocampal dentate granule cell excitability, with a focus on the neuronal glutamate transporter excitatory amino acid transporter 3 (EAAT3) and group I metabotropic glutamate receptors (mGluRs). Five days of repeated swim exposure increased spike firing in mature dentate granule cells from wild-type mice. PKN1a knockout produced a similar increase, and repeated swim did not further enhance firing in knockout mice. The enhanced firing observed after repeated swim exposure and in PKN1a knockout mice was reduced by co-application of an mGluR1 antagonist (LY367385) and an mGluR5 antagonist (MPEP). Inhibition of glutamate transporters with DL-TBOA increased granule cell firing in control wild-type mice but did not further increase firing in repeated-swim wild-type or PKN1a knockout mice, suggesting occlusion of transporter-dependent regulation of excitability. Repeated swim exposure and PKN1a knockout also reduced total and surface expression of EAAT3 in the hippocampus, whereas expression of the glial glutamate transporter EAAT2 was not significantly altered. Finally, PKN1a knockout and repeated swim exposure reduced anxiety-related behavior in the elevated plus maze test. Thus, PKN1a-dependent regulation of EAAT3 may restrain group I mGluR-dependent excitability in dentate granule cells, whereas repeated swim exposure and PKN1a knockout shift this system toward a lower-EAAT3, higher-excitability state accompanied by reduced anxiety-related behavior.

NMDAR and LGI1 encephalitis are the two most common forms of autoimmune encephalitis and are associated with persistent cognitive sequelae, particularly episodic memory impairment. Patients also report lasting difficulties with spatial orientation and navigation, yet these symptoms remain poorly characterized. Both disorders affect neural systems supporting spatial navigation, including prominent hippocampal pathology alongside cingulate, temporo-parietal, thalamic and cerebellar alterations identified in advanced neuroimaging studies. Here, we therefore investigated the frequency and clinical relevance of spatial navigation impairment in post-acute NMDAR and LGI1 encephalitis, its relationship with episodic memory dysfunction, and its structural correlates. We included 80 post-acute patients from the autoimmune encephalitis outpatient clinic at Charite - Universitatsmedizin Berlin: 50 with NMDAR encephalitis (mean age 35.0 years, range 19-71; 90% female; median 6.9 years from onset) and 30 with LGI1 encephalitis (mean age 63.6 years, range 33-84; 67% male; median 2.7 years from onset). Spatial navigation was assessed using a passive map-assisted task (VIENNA Young) and an active wayfinding task (Sea Hero Quest), and its relationship with verbal episodic memory was examined using the Rey Auditory Verbal Learning Test. Structural MRI analyses assessed cortical thickness, subcortical volumes and diffusion measures in preselected navigation- and memory-related regions. Patients with NMDAR and LGI1 encephalitis performed worse than matched controls on map-assisted navigation, and navigation performance showed strong convergence across the two navigation paradigms. Norm-referenced navigation impairment affected 57% of patients with NMDAR encephalitis and 70% with LGI1 encephalitis. In NMDAR encephalitis, selective navigation impairment was more common than selective memory impairment (41% versus 14%; {chi}2 = 6.26, p = .012), supporting partial dissociation. In LGI1 encephalitis, navigation and memory impairments were similarly frequent and strongly overlapping, with 53% of patients impaired in both domains. Older age was a shared risk factor for navigation impairment. Structurally, NMDAR encephalitis showed partly distinct navigation- and memory-related alteration patterns, with navigation-specific parietal-paracentral and cerebellar abnormalities and memory-specific temporal-hippocampal-thalamic involvement. LGI1 encephalitis showed more widespread, predominantly memory-related alterations without a robust navigation-specific structural signature. Our findings identify spatial navigation as a frequently affected but under-assessed cognitive domain in post-acute NMDAR and LGI1 encephalitis. They provide clinical evidence that navigation and episodic memory are partially dissociable yet overlapping functions whose degree of separability varies with the extent and distribution of network pathology. Incorporating norm-referenced navigation assessment into longitudinal follow-up could improve the characterization of cognitive profiles and related support needs, while reducing the risk that impairments relevant to everyday functioning and long-term quality of life remain undetected.

Healthy older adults are more susceptible to false memories than young adults. Traditional false memory paradigms leverage semantic overlap, shared meaning, to induce false memories, but experiences can also overlap temporally whereby they occur close together in time. Prior work shows that older adults have impaired episodic memory, memory for events within a spatiotemporal context, corresponding to an overall shift toward semantic memory and away from episodic memory across the lifespan. We hypothesize that compared to young adults, older adults rely more heavily on semantic versus episodic information, which promotes false memory. We collected behavioral data in young and older adults performing an old/new recognition memory task in which we manipulated the degree of semantic and temporal overlap between study words and included critical lures, unstudied words that semantically overlap with study words. We find that whereas young and older adults are similarly reliant on semantic relative to episodic information to support false memory, the two age groups differ in their reliance on semantic relative to episodic information to support true memory. These results suggest that differences in the orientation of attention -- toward semantic vs. episodic information -- may underlie age-related memory changes.

Excitation/inhibition (E/I) balance in cortical circuits is typically treated as a global neuronal property, yet pyramidal neurons integrate synaptic inputs from anatomically distinct afferent pathways whose regulation may not be uniform. Using a mouse model with early postnatal NMDA receptor (NMDAR) ablation from corticolimbic GABAergic interneurons associated E/I dysfunction, we tested whether interneuron NMDAR hypofunction disrupts the mPFC E/I balance globally or in a pathway-specific manner. Here, we use pathway-specific anatomical labeling, optogenetic circuit mapping, paired pyramidal neuron-fast spiking interneuron recordings, and analysis of synaptic integration and found that both structural and functional E/I imbalance emerged selectively at ventral hippocampal (vHPC) inputs onto mPFC pyramidal neurons, while callosal (contralateral mPFC) inputs remained unaffected. Structurally, this imbalance was restricted to vHPC-derived synapses on apical, but not basal, dendrites. Functionally, mutant mice showed an excitation-shifted E/I ratio specific to vHPC-driven responses, arising from a marked failure to recruit feedforward inhibition via fast-spiking interneurons, whose preferential excitatory drive from vHPC inputs was selectively lost. Short-term synaptic plasticity of vHPC and callosal inputs onto both pyramidal neurons and fast spiking interneurons was unchanged, indicating that presynaptic release dynamics could not account for the deficit. Consistent with impaired feedforward inhibition, pharmacological GABA-A receptor blockade failed to prolong vHPC-evoked EPSPs in mutant pyramidal neurons, in contrast to its clear effect on callosal-evoked responses, demonstrating that inhibitory control over the temporal integration of hippocampal, but not callosal, inputs was lost. Altogether, these findings establish pathway-specific E/I imbalance as a consequence of interneuron NMDAR hypofunction, and thus indicating that circuit dysfunction can selectively bias processing of specific afferent pathways rather than producing a uniform disruption of cortical excitability, with direct relevance for understanding hippocampal-prefrontal dysconnectivity in neuropsychiatric disorders.

Working memory is capacity-limited, but interactions with episodic memory may offset this constraint. We tested moment-by-moment contributions of episodic representations to working memory by combining the N-back and Mnemonic Similarity tasks. Thirty-one participants, undergoing eye-tracking, first encoded items in a one-back task, classifying them as "same" or "similar" to their predecessor. In a subsequent two-back task, mnemonic discrimination showed a graded, item-specific benefit of prior experience: performance was best for previously compared items, whereas recognition of identical repeats was unaffected. Successful discrimination of previously compared items was accompanied by greater pupil dilation, gradually emerging gaze patterns resembling those elicited by their similar pair-mate, and higher gaze-similarity between one-back and two-back target viewing. Diverging gaze patterns between pair-mates during one-back further predicted two-back discrimination. These findings challenge working memory's characterization as an isolated system, demonstrating how it recruits episodic computations - encoding distinct traces, predicting upcoming content, and reinstating it at retrieval.

Biological neurons can perform nonlinear computations within their dendrites and support branch-localized plasticity. This raises the possibility that single cells can store memories more efficiently and with less interference by confining synaptic modifications to specific dendrites. We study a parallel-dendrite model performing online familiarity detection and compare three dendrite-update rules during learning: (i) independent thresholding, (ii) an interacting rule that adapts the target local dendritic activation per item, and (iii) an interacting n-winners-take-all (WTA) rule that constrains the number of updated branches per item. The interacting rules substantially improve capacity by limiting variance in memory responses and decorrelating weights across branches -- even when inputs are strongly correlated. These results suggest that competition among dendrites, consistent with resource-limited plasticity mechanisms, can enhance single-cell memory beyond non-interacting schemes.

Sleepiness is a leading proximate cause of drowsy-driving fatalities, medical errors and industrial accidents, yet it has resisted mechanistic prediction; although it arises from well-characterized sleep-wake physiology, it is experienced as a subjective state and has lacked a quantitative link to the underlying dynamics. We previously showed that subjective sleepiness maps linearly, with a protocol-invariant form, onto the signed distance H - H+ between the homeostatic pressure H and the circadian-modulated sleep-onset threshold H+. This single quantity predicts sleepiness accurately but is mechanistically ambiguous: the same value can arise either because H sits far from the boundary or because the threshold H+(t) has shifted with circadian phase, and these two origins call for entirely different interpretations and interventions. Here we resolve this ambiguity by decomposing H - H+ into two mechanistically separable axes-intensity and phase. The intensity axis is the time-averaged margin [<] H - H+[>], set by how far, on average, H sits from the sleep boundary: slowed homeostatic accumulation accounts for the paradoxically blunted sleepiness of older adults, and pharmacological suppression of H accounts for the dose-dependent alerting effect of caffeine. The phase axis is set by the circadian modulation of H+(t): under a forced-desynchrony protocol, in which the pacemaker free-runs and the homeostatic and circadian processes are experimentally decoupled, sleepiness tracks the circadian profile of H+(t) across all phases while the intensity mapping itself remains unchanged-a clean dissociation of the two axes. By resolving felt sleepiness into these two physiological degrees of freedom, this framework renders previously isolated phenomena-aging, caffeine and circadian misalignment-commensurable within a single theory and provides a physiologically interpretable basis for prospective fatigue-risk prediction. Author summaryWhy people feel sleepy after sleep loss, or at particular times of day, remains difficult to predict from physiology alone. Sleep and wake are shaped by two interacting processes: a daily circadian rhythm and a homeostatic pressure that builds during wakefulness. In earlier work, we linked subjective sleepiness ratings to a simple geometric quantity-how close sleep pressure sits to a circadian sleep-onset boundary. That link is useful, but ambiguous: the same distance can arise either because pressure itself has changed, or because the boundary has moved with circadian phase. Here we use a computational model of the sleep-wake switch, extended to include the wake-stabilizing orexin system, to separate these contributions into an intensity axis and a phase axis. We find that aging and caffeine mainly alter how large the average distance to the boundary becomes, whereas forced desynchrony mainly alters how that distance varies across circadian phase. This dissociation offers a compact way to interpret several otherwise separate observations within one quantitative picture, and a step toward more physiologically grounded fatigue-risk assessment.

While loss of NMDA receptors (NMDARs) is associated with Alzheimers disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Exam (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the CA1 field. However, there was a significant diagnosis by sex interaction driven by sex-specific changes in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that changes in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.

Multiple lines of evidence point to the volume regulated anion channel (VRAC) as being instrumental for cellular volume regulation in many cell types, including astrocytes. VRAC are thought to open during periods of astrocyte swelling, releasing anions and osmolytes to drive water out of the cell, allowing it to return to baseline volume even under sustained osmotic or ionic challenge, a process called regulatory volume decrease, or RVD. However, the occurrence of RVD and VRACs role in this process has remained controversial, with clear evidence in cultured cells but mixed reports from work in intact brain tissue. In the present study, we aimed to address this gap by generating a transgenic mouse line in which VRAC is conditionally ablated in astrocytes (VRAC cKO) and recording the volume responses of astrocytes in VRAC cKO and control tissue using real-time volume imaging. We found that the effect of VRAC cKO on astrocyte swelling was dependent on whether swelling was evoked by elevated extracellular potassium, or by reduced extracellular osmolarity. We also found that both VRAC and the presence of sufficient intracellular taurine concentration were required to elicit RVD in astrocytes, but only in hypoosmolar conditions. Our findings provide new information on the conditions needed to elicit RVD in intact brain tissue, and that VRAC is required for RVD to occur. Our findings further suggest that reduction of intracellular ion concentration is essential for VRAC to be activated, rather than simply membrane expansion. Future experiments will examine the solute release aspect of VRAC activation upon astrocyte swelling, as well as the contributions of VRAC to pathological volume dysregulation.

Primary cilia, which are present in most brain cells, are essential for brain development and function. During early brain development, dysfunction of the primary cilia can lead to a broad spectrum of disorders, collectively termed ciliopathies, that include brain malformations and intellectual disability. Although the role of primary cilia in brain development is well-established, cilia-mediated signaling in mature neurons and the contribution of cilia to neuronal circuit function remain controversial. Using mouse genetic and behavioral studies, single-cell electrophysiology, and 2-photon imaging, we show that deletion of primary cilia from adult hippocampal neurons is not required for hippocampal circuit function or behavior. Chronic genetic deletion or acute laser ablation of primary cilia from mature pyramidal neurons in the CA1 or CA3 regions of the hippocampus did not affect neuronal excitability, basal synaptic transmission, or long-term synaptic plasticity at excitatory CA3-CA1 hippocampal synapses. Moreover, the loss of primary cilia did not affect hippocampal-dependent learning and memory or anxiety-like behaviors. These results challenge the prevailing view of cilia function in mature hippocampal neurons and suggest that neuronal cilia in the adult hippocampus do not serve as major signaling hubs for pathways essential for neuronal function or behavior.

Decades of developmental memory research has mainly reported linear and protracted changes in both human hippocampal function and connectivity between the hippocampus and cortex. While foundational, very few studies have interrogated the reliability of hippocampal signals across age, and how this coincides with (or diverges from) age-related changes in connectivity to broader cortical networks supporting multiple memory systems. Here, utilizing movie-watching fMRI data in children 3 to 12 years and adults, we assessed hippocampal response stability using an inter-subject functional correlation (ISFC) approach, and then measured functional connectivity between the hippocampus and the Posterior Medial (PM) - Anterior Temporal (AT) cortical memory networks proposed to support episodic-like (PM) and semantic-like (AT) memory respectively. Results showed that hippocampal responses are stable in the youngest children, but bifurcate in 7 year olds, with half the subjects correlating most highly with younger and half with older age groups. Likewise, we found that while functional connectivity within the AT network is stable across development, connections between the anterior hippocampus and this network did not reach adult levels until around 7 years. Thus, while brain networks supporting semantic memory may be in place early, interactions with the hippocampus may not develop until after middle childhood, with an inflection point around 7 years of age.

Light history leaves persistent changes in circadian period, but where this history is stored remains unresolved. Suprachiasmatic nucleus (SCN) network models have often approached photoperiodic encoding through phase organization or coupling strength. We computationally tested slow adaptation of subregion-specific intrinsic periods as an alternative memory mechanism. The model asymmetrically couples dorsal (D) and ventral (V) SCN oscillators and adds a systemic oscillator (X) representing putative circadian feedback present in vivo but lost ex vivo. With a single parameter set, period adaptation captured the direction and approximate magnitude of behavioral aftereffects across photoperiod and T-cycle conditions. Adapting coupling strength instead of period failed to reproduce the V-leading-D phase order reported after T22. Removing systemic feedback preserved the photoperiod-dependent period ordering but inverted the T22 and T26 aftereffects, an inversion that matched SCN explant observations. The model also yielded distinct D-V phase organization for each of 18:6 LD, T23, and T25. These results suggest that subregion-specific period plasticity provides a parsimonious substrate for encoding light history, while the dependence on systemic feedback indicates that behavioral period may not be a readout of the SCN alone. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/743784v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@d48266org.highwire.dtl.DTLVardef@1bd15bdorg.highwire.dtl.DTLVardef@de3d9forg.highwire.dtl.DTLVardef@9fbc39_HPS_FORMAT_FIGEXP M_FIG C_FIG A model with dorsal period adaptation and phenomenological systemic feedback accounts for behavioral and explanted SCN aftereffects. (A) During T22 entrainment, dorsal (D), ventral (V), and systemic (X) oscillators remain phase-locked. After release into constant darkness, systemic coupling maintains a unified in vivo rhythm, whereas removing X feedback in the explant simulation allows the D-V network to express a distinct ex vivo period aftereffect. (B) The SCN model is modeled as an asymmetrically coupled attractive-repulsive oscillator network with stronger photic input to V. Light history is encoded via plasticity of the intrinsic period in D, while X represents putative systemic circadian feedback available in vivo and lacking direct photic input. (C) The model reproduces concordant period changes in behavior and SCN explants across photoperiods, but opposing period changes following T-cycle entrainment.

Long-term depression (LTD) is a form of synaptic plasticity implicated in tasks involving the modification or elimination of previously learned information. While glial glutamate transporters can control the strength of synaptic plasticity, much less is known about the contribution of the neuronal glutamate transporter EAAT3 in controlling hippocampal LTD and learning processes. Here, we report that overexpression of EAAT3 in principal neurons, but not in GABAergic interneurons, impairs heterosynaptic GABAergic synaptic plasticity (iLTD) and homosynaptic excitatory LTD in the hippocampus. LTD impairments can be reversed by inhibiting EAAT3 or by a brief exogenous activation of mGluR during LTD induction, suggesting that, by limiting glutamate spillover between neighboring synapses, EAAT3 contributes to setting the strength of different forms of hippocampal LTD. Moreover, mice overexpressing EAAT3 in principal neurons, but not in GABAergic interneurons, display impaired reversal learning, a phenotype that can be rescued by blocking EAAT3 in vivo. Together, these findings reveal that, by controlling the strength of hippocampal LTD, EAAT3 contributes to cognitive flexibility required for processing new information.