Extrahippocampal Regions Research Articles

Contribution of the lateral occipital and parahippocampal cortices to pattern separation of objects and contexts.

Contextual features are integral to episodic memories; yet, we know little about context effects on pattern separation, a hippocampal function promoting orthogonalization of overlapping memory representations. Recent studies suggested that various extrahippocampal brain regions support pattern separation; however, the specific role of the parahippocampal cortex-a region involved in context representation-in pattern separation has not yet been studied. Here, we investigated the contribution of the parahippocampal cortex (specifically, the parahippocampal place area) to context reinstatement effects on mnemonic discrimination, using functional magnetic resonance imaging. During scanning, participants saw object images on unique context scenes, followed by a recognition task involving the repetitions of encoded objects or visually similar lures on either their original context or a lure context. Context reinstatement at retrieval improved item recognition but hindered mnemonic discrimination. Crucially, our region of interest analyses of the parahippocampal place area and an object-selective visual area, the lateral occipital cortex indicated that while during successful mnemonic decisions parahippocampal place area activity decreased for old contexts compared to lure contexts irrespective of object novelty, lateral occipital cortex activity differentiated between old and lure objects exclusively. These results imply that pattern separation of contextual and item-specific memory features may be differentially aided by scene and object-selective cortical areas.

ANTsX neuroimaging-derived structural phenotypes of UK Biobank

UK Biobank is a large-scale epidemiological resource for investigating prospective correlations between various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multiple modalities provides imaging-derived phenotypes (IDPs) that can serve as biomarkers in neuroscience research. In this study, we augment the existing set of UK Biobank neuroimaging structural IDPs, obtained from well-established software libraries such as FSL and FreeSurfer, with related measurements acquired through the Advanced Normalization Tools Ecosystem. This includes previously established cortical and subcortical measurements defined, in part, based on the Desikan-Killiany-Tourville atlas. Also included are morphological measurements from two recent developments: medial temporal lobe parcellation of hippocampal and extra-hippocampal regions in addition to cerebellum parcellation and thickness based on the Schmahmann anatomical labeling. Through predictive modeling, we assess the clinical utility of these IDP measurements, individually and in combination, using commonly studied phenotypic correlates including age, fluid intelligence, numeric memory, and several other sociodemographic variables. The predictive accuracy of these IDP-based models, in terms of root-mean-squared-error or area-under-the-curve for continuous and categorical variables, respectively, provides comparative insights between software libraries as well as potential clinical interpretability. Results demonstrate varied performance between package-based IDP sets and their combination, emphasizing the need for careful consideration in their selection and utilization.

Interhemispheric asymmetrical change in gray matter volume in patients with unilateral hippocampal sclerosis.

To clarify the interhemispheric asymmetrical change in gray matter volume (GMV) in unilateral hippocampal sclerosis (HS), we compared changes in GMV relative to normal subjects between the HS and contralateral or non-HS sides. Forty-five patients with unilateral HS and 30 healthy subjects were enrolled. We quantified changes in GMV in the patients with HS as compared to GMV in the normal subjects by introducing the Z-score (Z-GMV) in each region or region of interest in unilateral HS. Then, we assessed the asymmetrically decreased regions, that is, regions with significantly higher Z-GMV on the HS side than the contralateral or non-HS side. Z-GMV was calculated according to the two templates of 58 regions per hemisphere covering the whole brain by anatomical automatic labeling (AAL) and 78 regions per cerebral hemisphere using the Anatomy Toolbox. Seven and four regions in AAL and 17 and 11 regions in Anatomy Toolbox were asymmetrically decreased in the Left Hand Side (LHS) and Right Hand Side (RHS), respectively. Hippocampus and Caudate in AAL, five subregions of the hippocampus (CA1-3, Dentate Gyrus and hippocampus-amygdala-transition-area and 4 extrahippocampal regions including two subregions in amygdala (CM: Centromedial, SF: Superficial), basal forebrain (BF) (Ch4), and thalamus (temporal) in anatomy toolbox were common among LHS and RHS concerning asymmetrically decreased regions. By introducing Z-GMV, we demonstrated the regions with asymmetrically decreased GMV in LHS and RHS, and found that the hippocampus and extrahippocampal regions, including the BF, were the common asymmetrically decreased regions among LHS and RHS.

Cardiorespiratory fitness is associated with cortical thickness of medial temporal brain areas associated with spatial cognition in young but not older adults.

Cardiorespiratory fitness has a potent effect on neurocognitive health, especially regarding the hippocampal memory system. However, less is known about the impact of cardiorespiratory fitness on medial temporal lobe extrahippocampal neocortical regions. Specifically, it is unclear how cardiorespiratory fitness modulates these brain regions in young adulthood and if these regions are differentially related to cardiorespiratory fitness in young versus older adults. The primary goal of this study was to investigate if cardiorespiratory fitness predicted medial temporal lobe cortical thickness which, with the hippocampus, are critical for spatial learning and memory. Additionally, given the established role of these cortices in spatial navigation, we sought to determine if cardiorespiratory fitness and medial temporal lobe cortical thickness would predict greater subjective sense of direction in both young and older adults. Cross-sectional data from 56 young adults (20-35 years) and 44 older adults (55-85 years) were included. FreeSurfer 6.0 was used to automatically segment participants' 3T T1-weighted images. Using hierarchical multiple regression analyses, we confirmed significant associations between greater cardiorespiratory fitness and greater left entorhinal, left parahippocampal, and left perirhinal cortical thickness in young, but not older, adults. Left parahippocampal cortical thickness interacted with age group to differentially predict subjective sense of direction in young and older adults. Young adults displayed a positive, and older adults a negative, correlation between left parahippocampal cortical thickness and sense of direction. Our findings extend previous work on the association between cardiorespiratory fitness and hippocampal subfield structure in young adults to left medial temporal lobe neocortical regions.

Simultaneous high-resolution whole-brain MR spectroscopy and [18F]FDG PET for temporal lobe epilepsy.

Precise lateralizing the epileptogenic zone in patients with drug-resistant mesial temporal lobe epilepsy (mTLE) remains challenging, particularly when routine MRI scans are inconclusive (MRI-negative). This study aimed to investigate the synergy of fast, high-resolution, whole-brain MRSI in conjunction with simultaneous [18F]FDG PET for the lateralization of mTLE. Forty-eight drug-resistant mTLE patients (M/F 31/17, age 12-58) underwent MRSI and [18F]FDG PET on a hybrid PET/MR scanner. Lateralization of mTLE was evaluated by visual inspection and statistical classifiers of metabolic mappings against routine MRI. Additionally, this study explored how disease status influences the associations between altered N-acetyl aspartate (NAA) and FDG uptake using hierarchical moderated multiple regression. The high-resolution whole-brain MRSI data offers metabolite maps at comparable resolution to [18F]FDG PET. Visual examinations of combined MRSI and [18F]FDG PET showed an mTLE lateralization accuracy rate of 91.7% in a 48-patient cohort, surpassing routine MRI (52.1%). Notably, out of 23 MRI-negative mTLE, combined MRSI and [18F]FDG PET helped detect 19 cases. Logistical regression models combining hippocampal NAA level and FDG uptake improved lateralization performance (AUC=0.856), while further incorporating extrahippocampal regions such as amygdala, thalamus, and superior temporal gyrus increased the AUC to 0.939. Concurrent MRSI/PET revealed a moderating influence of disease duration and hippocampal atrophy on the association between hippocampal NAA and glucose uptake, providing significant new insights into the disease's trajectory. This paper reports the first metabolic imaging study using simultaneous high-resolution MRSI and [18F]FDG PET, which help visualize MRI-unidentifiable lesions and may thus advance diagnostic tools and management strategies for drug-resistant mTLE.

Development of the hippocampal CA2 region and the emergence of social recognition.

Social memories formed in early life, like those for family and unrelated peers, are known to contribute to healthy social interactions throughout life, although how the developing brain supports social memory remains relatively unexplored. The CA2 subregion of the hippocampus is involved in social memory function, but most literature on this subject is restricted to studies of adult rodents. Here, we review the current literature on the embryonic and postnatal development of hippocampal subregion CA2 in mammals, with a focus on the emergence of its unusual molecular and cellular characteristics, including its notably high expression of plasticity-suppressing molecules. We also consider the connectivity of the CA2 with other brain areas, including intrahippocampal regions, such as the dentate gyrus, CA3, and CA1 regions, and extrahippocampal regions, such as the hypothalamus, ventral tegmental area, basal forebrain, raphe nuclei, and the entorhinal cortex. We review developmental milestones of CA2 molecular, cellular, and circuit-level features that may contribute to emerging social recognition abilities for kin and unrelated conspecifics in early life. Lastly, we consider genetic mouse models related to neurodevelopmental disorders in humans in order to survey evidence about whether atypical formation of the CA2 may contribute to social memory dysfunction.

Convolutional Neural Network Algorithm to Determine Lateralization of Seizure Onset in Patients With Epilepsy: A Proof-of-Principle Study.

A new frontier in diagnostic radiology is the inclusion of machine-assisted support tools that facilitate the identification of subtle lesions often not visible to the human eye. Structural neuroimaging plays an essential role in the identification of lesions in patients with epilepsy, which often coincide with the seizure focus. In this study, we explored the potential for a convolutional neural network (CNN) to determine lateralization of seizure onset in patients with epilepsy using T1-weighted structural MRI scans as input. Using a dataset of 359 patients with temporal lobe epilepsy (TLE) from 7 surgical centers, we tested whether a CNN based on T1-weighted images could classify seizure laterality concordant with clinical team consensus. This CNN was compared with a randomized model (comparison with chance) and a hippocampal volume logistic regression (comparison with current clinically available measures). Furthermore, we leveraged a CNN feature visualization technique to identify regions used to classify patients. Across 100 runs, the CNN model was concordant with clinician lateralization on average 78% (SD = 5.1%) of runs with the best-performing model achieving 89% concordance. The CNN outperformed the randomized model (average concordance of 51.7%) on 100% of runs with an average improvement of 26.2% and outperformed the hippocampal volume model (average concordance of 71.7%) on 85% of runs with an average improvement of 6.25%. Feature visualization maps revealed that in addition to the medial temporal lobe, regions in the lateral temporal lobe, cingulate, and precentral gyrus aided in classification. These extratemporal lobe features underscore the importance of whole-brain models to highlight areas worthy of clinician scrutiny during temporal lobe epilepsy lateralization. This proof-of-concept study illustrates that a CNN applied to structural MRI data can visually aid clinician-led localization of epileptogenic zone and identify extrahippocampal regions that may require additional radiologic attention. This study provides Class II evidence that in patients with drug-resistant unilateral temporal lobe epilepsy, a convolutional neural network algorithm derived from T1-weighted MRI can correctly classify seizure laterality.

Control of contextual memory through interneuronal α5-GABAA receptors.

γ-Aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABAARs) are highly enriched in the hippocampus and are strongly implicated in control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that mice in which α5-GABAARs have been eliminated from pyramidal neurons (α5-pyr-KO) continue to form strong spatial engrams and that they remain as sensitive as their pseudo-wild-type (p-WT) littermates to etomidate-induced suppression of place cells and spatial engrams. By contrast, mice with selective knockout in interneurons (α5-i-KO) no longer exhibit etomidate-induced suppression of place cells. In addition, the strength of spatial engrams is lower in α5-i-KO mice than p-WT littermates under control conditions. Consistent with the established role of the hippocampus in contextual fear conditioning, α5-i-KO mice resisted etomidate's suppression of freezing to context, but so too did α5-pyr-KO mice, supporting a role for extra-hippocampal regions in the development of contextual fear memory. Overall, our results indicate that interneuronal α5-GABAARs serve a physiological role in promoting spatial learning and that they mediate suppression of hippocampus-dependent contextual memory by etomidate.

Extra-hippocampal contributions to pattern separation.

Pattern separation, or the process by which highly similar stimuli or experiences in memory are represented by non-overlapping neural ensembles, has typically been ascribed to processes supported by the hippocampus. Converging evidence from a wide range of studies, however, suggests that pattern separation is a multistage process supported by a network of brain regions. Based on this evidence, considered together with related findings from the interference resolution literature, we propose the 'cortico-hippocampal pattern separation' (CHiPS) framework, which asserts that brain regions involved in cognitive control play a significant role in pattern separation. Particularly, these regions may contribute to pattern separation by (1) resolving interference in sensory regions that project to the hippocampus, thus regulating its cortical input, or (2) directly modulating hippocampal processes in accordance with task demands. Considering recent interest in how hippocampal operations are modulated by goal states likely represented and regulated by extra-hippocampal regions, we argue that pattern separation is similarly supported by neocortical-hippocampal interactions.

Ripple-selective GABAergic projection cells in the hippocampus

Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the invivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.

5-HT modulation of a medial septal circuit tunes social memory stability.

Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group1,2. The dorsal CA2 (dCA2)3-5 and ventral CA1 (vCA1)6 subregions of the hippocampus, and their projection targets6,7, have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT1B receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours8,9, but also social memory, by influencing distinct target structures.

Extrahippocampal Radiomics Analysis Can Potentially Identify Laterality in Patients With MRI-Negative Temporal Lobe Epilepsy.

Objective: The objective of the study was to investigate whether radiomics features of extrahippocampal regions differ between patients with epilepsy and healthy controls, and whether any differences can identify patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE).Methods: Data from 36 patients with hippocampal sclerosis (HS) and 50 healthy controls were used to construct a radiomics model. A total of 1,618 radiomics features from the affected hippocampal and extrahippocampal regions were compared with features from healthy controls and the unaffected side of patients. Using a stepwise selection method with a univariate t-test and elastic net penalization, significant predictors for identifying TLE were separately selected for the hippocampus (H+) and extrahippocampal region (H–). Each model was independently validated with an internal set of MRI-negative adult TLE patients (n = 22) and pediatric validation cohort with MRI-negative TLE (n = 20) from another tertiary center; diagnostic performance was calculated using area under the curve (AUC) of the receiver-operating-characteristic curve analysis.Results: Forty-eight significant H+ radiomic features and 99 significant H– radiomic features were selected from the affected side of patients and used to create a hippocampus model and an extrahippocampal model, respectively. Texture features were the most frequently selected feature. Training set showed slightly higher accuracy between hippocampal (AUC = 0.99) and extrahippocampal model (AUC = 0.97). In the internal validation and external validation sets, the extrahippocampal model (AUC = 0.80 and 0.92, respectively) showed higher diagnostic performance for identifying the affected side of patients than the hippocampus model (AUC = 0.67 and 0.69).Significance: Radiomics revealed extrahippocampal abnormality in the affected side of patients with TLE and could potentially help to identify MRI-negative TLE.Classification of Evidence: Class IV Criteria for Rating Diagnostic Accuracy Studies.

Differential regulation of excitatory synaptic transmission in the hippocampus and anterior temporal lobe by cyclin dependent kinase 5 (Cdk5) in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS)

Mesial temporal lobe epilepsy with hippocamapal sclerosis (MTLE-HS) is the most common form of drug resistant epilepsy (DRE). MTLE-HS is a distributed network disorder comprising of not only the hippocampus, but other anatomically related extrahippocampal regions. Excitatory synaptic transmission is differentially regulated in the hippocampal and extra-hippocampal regions of patients with MTLE-HS, but its mechanism not understood. Cyclin-dependent kinase 5 (Cdk5) is known to regulate synaptic transmission and plasticity through up-regulation of NMDA receptors by phosphorylating NR2Asubunits. The present study is designed to investigate whether Cdk5 differentially regulates the excitatory synaptic transmission in the hippocampus and anterior temporal lobe (ATL) samples obtained from patients of MTLE-HS. We have measured the Cdk5 kinase activity and the protein levels of Cdk5, p-Cdk5, p35/p25, NR2A, pNR2A in the hippocampal and ATL samples obtained from patients with MTLE-HS. We have also determined the effect of roscovitine, a Cdk5 antagonist, on spontaneous excitatory postsynaptic currents (EPSCs) recorded from the hippocampal and ATL using patch-clamp technique. We observed significant increase in the expression of Cdk5, p-Cdk5, p35/p25, NR2A, pNR2A in the ATL samples as compared to the hippocampal samples. Cdk5 activity was significantly higher in ATL samples as compared to the hippocampal samples. Magnitude of reduction in the frequency of EPSCs by roscovitine in the ATL samples was higher than that in the hippocampal samples. Our studies suggest that Cdk5 differentially regulates excitatory synaptic activity in the hippocampal and ATL region of patients with MTLE-HS.

Usefulness of magnetic resonance spectroscopy in mesial temporal sclerosis: a systematic review.

Magnetic resonance spectroscopy (MRS) provides non-invasive information about metabolic features in different regions of the brain affected by mesial temporal sclerosis (MTS). To review articles analyzing the most common alterations in biochemical parameters in MTS and the applications of MRS in presurgical assessment. We undertook a systematic literature search for MRS in MTS in PubMed, SCOPUS, and Cochrane based on the MESH terms ""Magnetic Resonance Spectroscopy", "Proton Magnetic Resonance Spectroscopy", "Carbon-13 Magnetic Resonance Spectroscopy", "1H-MRS", "31P-MRS", "mesial temporal sclerosis", "hippocampal sclerosis", "mesial temporal seizure", and "mesial temporal epilepsy". Of the initial 134 articles found, 30 were selected after the exclusion process. Of these, 13 detected a decrease in N-acetylaspartate (NAA), 9 showed a decreased in the ratio NAA/Cho+Cr, and 8 demonstrated a decreased in the ratio NAA/Cr, all of them in the ipsilateral hippocampus. Nine studies also found reduced NAA levels in extrahippocampal regions. The main findings were a decrease in NAA in the ipsilateral hippocampus. In addition, NAA levels were low outside the hippocampus so MTS could be a more extensive disease. Patients without MTS also presented a decrease in NAA in the ipsilateral hippocampus although NAA was even lower in the MTS patients. Thus, MRS could be useful in the presurgical evaluation to locate the epileptogenic focus, but not specific for the diagnosis of MTS.

Emotional arousal impairs association memory: roles of prefrontal cortex regions.

The brain processes underlying impairing effects of emotional arousal on associative memory were previously attributed to two dissociable routes using high-resolution fMRI of the MTL (Madan et al. 2017). Extrahippocampal MTL regions supporting associative encoding of neutral pairs suggested unitization; conversely, associative encoding of negative pairs involved compensatory hippocampal activity. Here, whole-brain fMRI revealed prefrontal contributions: dmPFC was more involved in hippocampal-dependent negative pair learning and vmPFC in extrahippocampal neutral pair learning. Successful encoding of emotional memory associations may require emotion regulation/conflict resolution (dmPFC), while neutral memory associations may be accomplished by anchoring new information to prior knowledge (vmPFC).

Role of Modulation of Hippocampal Glucose Following Pilocarpine-Induced Status Epilepticus.

Status epilepticus (SE) is defined as continuous and self-sustaining seizures, which trigger hippocampal neurodegeneration, mitochondrial dysfunction, oxidative stress, and energy failure. During SE, the neurons become overexcited, increasing energy consumption. Glucose uptake is increased via the sodium glucose cotransporter 1 (SGLT1) in the hippocampus under epileptic conditions. In addition, modulation of glucose can prevent neuronal damage caused by SE. Here, we evaluated the effect of increased glucose availability in behavior of limbic seizures, memory dysfunction, neurodegeneration process, neuronal activity, and SGLT1 expression. Vehicle (VEH, saline 0.9%, 1μL) or glucose (GLU; 1, 2 or 3mM, 1μL) were administered into hippocampus of male Wistar rats (Rattus norvegicus) before or after pilocarpine to induce SE. Behavioral analysis of seizures was performed for 90min during SE. The memory and learning processes were analyzed by the inhibitory avoidance test. After 24h of SE, neurodegeneration process, neuronal activity, and SGLT1 expression were evaluated in hippocampal and extrahippocampal regions. Modulation of hippocampal glucose did not protect memory dysfunction followed by SE. Our results showed that the administration of glucose after pilocarpine reduced the severity of seizures, as well as the number of limbic seizures. Similarly, glucose after SE reduced cell death and neuronal activity in hippocampus, subiculum, thalamus, amygdala, and cortical areas. Finally, glucose infusion elevated the SGLT1 expression in hippocampus. Taken together our data suggest that possibly the administration of intrahippocampal glucose protects brain in the earlier stage of epileptogenic processes via an important support of SGLT1.

Differential Expression of the Metabotropic P2Y Receptor Family in the Cortex Following Status Epilepticus and Neuroprotection via P2Y1 Antagonism in Mice.

Purinergic signaling via P2 receptors is now widely accepted to play a critical role during increased states of hyperexcitability and seizure-induced pathology. In the setting of seizures and epilepsy, most attention has been paid to investigating the fast-acting ATP-gated P2X receptor family. More recent evidence has now also provided compelling evidence of an involvement of the slower-acting P2Y receptor family during seizures. This includes data demonstrating expression changes of P2Y receptors in the hippocampus following acute seizures and during epilepsy and anticonvulsive properties of P2Y-targeting drugs; in particular drugs targeting the P2Y1 subtype. Seizures, however, also involve damage to extra-hippocampal brain regions such as the cortex, which is thought to contribute to the epileptic phenotype. To analyze expressional changes of the P2Y receptor family in the cortex following status epilepticus and to determine the impact of drugs interfering with P2Y1 signaling on cortical damage, we used a unilateral mouse model of intraamygdala kainic acid-induced status epilepticus. Analysis of cortical tissue showed that status epilepticus leads to a global up-regulation of the P2Y receptor family in the cortex including P2Y1, P2Y2, P2Y4, and P2Y6, with the P2Y1 and P2Y4 receptor subtypes showing the strongest increase. Supporting a detrimental role of P2Y1 activation during status epilepticus, treatment with the P2Y1 agonist MRS2365 exacerbated high frequency high amplitude spiking, synonymous with injury-causing electrographic activity, and treatment with the P2Y1 antagonists MRS2500 protected against seizure-induced cortical damage. Suggesting P2Y1-mediated effects are predominantly due to increased microglia activation, treatment with the broad-spectrum anti-inflammatory drug minocycline abolished the observed neuroprotective effects of P2Y1 antagonism. In conclusion, our results further support a role for P2Y1-mediated signaling during seizure generation and seizure-induced neurodegeneration, suggesting P2Y1-targeting therapies as novel treatment for drug-refractory status epilepticus.

Novel long-range inhibitory nNOS-expressing hippocampal cells.

The hippocampus, a brain region that is important for spatial navigation and episodic memory, benefits from a rich diversity of neuronal cell-types. Through the use of an intersectional genetic viral vector approach in mice, we report novel hippocampal neurons which we refer to as LINCs, as they are long-range inhibitory neuronal nitric oxide synthase (nNOS)-expressing cells. LINCs project to several extrahippocampal regions including the tenia tecta, diagonal band, and retromammillary nucleus, but also broadly target local CA1 cells. LINCs are thus both interneurons and projection neurons. LINCs display regular spiking non-pyramidal firing patterns, are primarily located in the stratum oriens or pyramidale, have sparsely spiny dendrites, and do not typically express somatostatin, VIP, or the muscarinic acetylcholine receptor M2. We further demonstrate that LINCs can strongly influence hippocampal function and oscillations, including interregional coherence. The identification and characterization of these novel cells advances our basic understanding of both hippocampal circuitry and neuronal diversity.

Occurrence of Hippocampal Ripples is Associated with Activity Suppression in the Mediodorsal Thalamic Nucleus.

Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal-prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus and the mPFC at different stages of information processing. Here, we characterized, in freely behaving Sprague Dawley male rats, the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal-cortical information transfer. Overall, the MD firing rate was transiently (0.76 ± 0.06 s) decreased around ripples, with the MD activity suppression preceding the ripple onset for 0.41 ± 0.04 s (range, 0.01-0.95 s). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal-cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During non-rapid eye movement sleep, MD firing rate decreased around spindle-uncoupled ripples, but increased around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamocortical and hippocampal-cortical networks supporting "on-line" and "off-line" information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay, as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments.SIGNIFICANCE STATEMENT Systems mechanisms of declarative memory consolidation beyond the hippocampal-prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extrahippocampal regions and with medial prefrontal cortex underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in "off-line" consolidation. We found that MD neural activity was transiently suppressed around hippocampal ripples, except for ripples co-occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay, as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer.

The Rhesus Monkey Hippocampus Critically Contributes to Scene Memory Retrieval, But Not New Learning.

Humans can recall a large number of memories years after the initial events. Patients with amnesia often have lesions to the hippocampus, but human lesions are imprecise, making it difficult to identify the anatomy underlying memory impairments. Rodent studies enable great precision in hippocampal manipulations, but not investigation of many interleaved memories. Thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. Furthermore, disagreement exists as to whether hippocampal inactivations lead to temporally graded or ungraded amnesia, which could be a consequence of differences between rodent and human studies. In the current study, rhesus monkeys of both sexes received either bilateral neurotoxic hippocampal lesions or remained unoperated controls and were tested on recognition and new learning of visual object-in-place scenes. Monkeys with hippocampal lesions were significantly impaired at remembering scenes that were encoded before the lesion. We did not observe any temporal gradient effect of the lesion on memory recognition, with recent and remote memories being equally affected by the lesion. Monkeys with hippocampal lesions showed no deficits in learning new scenes. Thus, the hippocampus, like other cortical regions, may be engaged in the acquisition and storage of new memories, but the role of the damaged hippocampus can be taken over by spared hippocampal tissue or extra-hippocampal regions following a lesion. These findings illustrate the utility of experimental paradigms for studying retrograde and anterograde amnesia that make use of the capacity of nonhuman primates to rapidly acquire many distinct visual memories.SIGNIFICANCE STATEMENT Recalling old memories, creating new memories, and the process by which memories transition from temporary to permanent storage all may rely on the hippocampus. Whether the hippocampus is necessary for encoding and retrieval of multiple related visual memories in primates is not known. Monkeys that learned many visual memory problems before precise lesions of the hippocampus were impaired at recalling those memories after hippocampal damage regardless of when the memories were formed, but could learn new memory problems at a normal rate. This suggests the hippocampus is normally vital for retrieval of complex visual memories regardless of their age, and also points to the importance of investigating mechanisms by which memories may be acquired in the presence of hippocampal damage.