Physiological characteristics of neurons in the mammillary bodies align with topographical organization of subicular inputs.

The mammillary bodies (MBOs), a group of hypothalamic nuclei, play a pivotal role in memory formation and spatial navigation. They receive extensive inputs from the hippocampus through the fornix, but the physiological significance of these connections remains poorly understood. Damage to the MBOs is associated with various forms of anterograde amnesia.

Mixing novel and familiar cues modifies representations of familiar visual images and affects behavior.

While visual responses to familiar and novel stimuli have been extensively studied, it is unknown how neuronal representations of familiar stimuli are affected when they are interleaved with novel images. We examined a large-scale dataset from mice performing a visual go/no-go change detection task. After training with eight images, six novel images were interleaved with two familiar ones.

Simple Behavioral Analysis (SimBA) as a platform for explainable machine learning in behavioral neuroscience.

The study of complex behaviors is often challenging when using manual annotation due to the absence of quantifiable behavioral definitions and the subjective nature of behavioral annotation. Integration of supervised machine learning approaches mitigates some of these issues through the inclusion of accessible and explainable model interpretation. To decrease barriers to access, and with an emphasis on accessible model explainability, we developed the open-source Simple Behavioral Analysis (SimBA) platform for behavioral neuroscientists.

Functional specialization of hippocampal somatostatin-expressing interneurons.

Hippocampal somatostatin-expressing () GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single-cell transcriptome analyses have provided a comprehensive -IN subpopulations census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations of -INs based on transcriptomic features.

Presynaptic Protein Synthesis in Brain Function and Disease.

Local protein synthesis in mature brain axons regulates the structure and function of presynaptic boutons by adjusting the presynaptic proteome to local demands. This crucial mechanism underlies experience-dependent modifications of brain circuits, and its dysregulation may contribute to brain disorders, such as autism and intellectual disability. Here, we discuss recent advancements in the axonal transcriptome, axonal RNA localization and translation, and the role of presynaptic local translation in synaptic plasticity and memory.

Hippocampal sharp-wave ripples and their spike assembly content are regulated by the medial entorhinal cortex.

Hippocampal sharp-wave ripples (SPW-Rs) are critical for memory consolidation and retrieval. The neuronal content of spiking during SPW-Rs is believed to be under the influence of neocortical inputs via the entorhinal cortex (EC). Optogenetic silencing of the medial EC (mEC) reduced the incidence of SPW-Rs with minor impacts on their magnitude or duration, similar to local CA1 silencing.

Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells.

In eukaryotes, carnitine is best known for its ability to shuttle esterified fatty acids across mitochondrial membranes for β-oxidation. It also returns to the cytoplasm, in the form of acetyl-L-carnitine (LAC), some of the resulting acetyl groups for posttranslational protein modification and lipid biosynthesis. While dietary LAC supplementation has been clinically investigated, its effects on cellular metabolism are not well understood.

Oxytocin-Modulated Ion Channel Ensemble Controls Depolarization, Integration and Burst Firing in CA2 Pyramidal Neurons.

Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity.

The three-dimensional landscape of cortical chromatin accessibility in Alzheimer's disease.

To characterize the dysregulation of chromatin accessibility in Alzheimer's disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer-promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome).

Extrinsic control and intrinsic computation in the hippocampal CA1 circuit.

In understanding circuit operations, a key problem is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. We addressed this issue in the hippocampus by performing combined optogenetic and pharmacogenetic local and upstream inactivation. Silencing the medial entorhinal cortex (mEC) largely abolished extracellular theta and gamma currents in CA1 while only moderately affecting firing rates.

Multidimensional predictors of antidepressant responses: Integrating mitochondrial, genetic, metabolic and environmental factors with clinical outcomes.

Major depressive disorder (MDD) is a primary psychiatric illness worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Although we continue to discover individual biological factors, a major challenge is the identification of integrated, multidimensional traits underlying the complex heterogeneity of depression and treatment outcomes. Here, we set out to ascertain the emergence of the novel mitochondrial mediator of epigenetic function acetyl-L-carnitine (LAC) in relation to previously described individual predictors of antidepressant responses to the insulin-sensitizing agent pioglitazone.

Off-Target Expression of Cre-Dependent Adeno-Associated Viruses in Wild-Type C57BL/6J Mice.

Adeno-associated viruses (AAVs) are a commonly used tool in neuroscience to efficiently label, trace, and/or manipulate neuronal populations. Highly specific targeting can be achieved through recombinase-dependent AAVs in combination with transgenic rodent lines that express Cre-recombinase in specific cell types. Visualization of viral expression is typically achieved through fluorescent reporter proteins (e.

Gamma rhythm communication between entorhinal cortex and dentate gyrus neuronal assemblies.

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner.

Unique dynamics and exocytosis properties of GABAergic synaptic vesicles revealed by three-dimensional single vesicle tracking.

Maintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system. Inhibitory synaptic transmission plays an important role in maintaining this balance. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood.

Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus.

Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long-range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG.

Bidirectional Regulation of Cognitive and Anxiety-like Behaviors by Dentate Gyrus Mossy Cells in Male and Female Mice.

The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs).

Hippocampal CA2 sharp-wave ripples reactivate and promote social memory.

The consolidation of spatial memory depends on the reactivation ('replay') of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples (SWRs)-synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep and whose disruption impairs spatial memory. Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories.

Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions.

Seizure incidence is increased in Alzheimer's disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of ΔFosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in ΔFosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy.

Synaptic Mechanisms Underlying the Network State-Dependent Recruitment of VIP-Expressing Interneurons in the CA1 Hippocampus.

Disinhibition is a widespread circuit mechanism for information selection and transfer. In the hippocampus, disinhibition of principal cells is provided by the interneuron-specific interneurons that express the vasoactive intestinal polypeptide (VIP-IS) and innervate selectively inhibitory interneurons. By combining optophysiological experiments with computational models, we determined the impact of synaptic inputs onto the network state-dependent recruitment of VIP-IS cells.

Excitatory/Inhibitory Responses Shape Coherent Neuronal Dynamics Driven by Optogenetic Stimulation in the Primate Brain.

Coherent neuronal dynamics play an important role in complex cognitive functions. Optogenetic stimulation promises to provide new ways to test the functional significance of coherent neural activity. However, the mechanisms by which optogenetic stimulation drives coherent dynamics remain unclear, especially in the nonhuman primate brain.

Utility of the Idling Brain: Abstraction of New Knowledge.

Using clever experimental design and exploiting the high temporal resolution power of magnetoencephalography, Liu et al. show in humans how "offline" reactivation of brain patterns allows the abstraction of new knowledge from previous experience. The key mechanism may involve hippocampal sharp-wave ripples.

Long-duration hippocampal sharp wave ripples improve memory.

Hippocampal sharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memory consolidation and action planning. The duration of ripples shows a skewed distribution with a minority of long-duration events. We discovered that long-duration ripples are increased in situations demanding memory in rats.