Assessment of social behavior and chemosensory cue detection in an animal model of neurodegeneration.

Numerous studies have shown that aging in humans leads to a decline in olfactory function, resulting in deficits in acuity, detection threshold, discrimination, and olfactory-associated memories. Furthermore, impaired olfaction has been identified as a potential indicator for the onset of age-related neurodegenerative diseases, including Alzheimer's disease (AD). Studies conducted on mouse models of AD have largely mirrored the findings in humans, thus providing a valuable system to investigate the cellular and circuit adaptations of the olfactory system during natural and pathological aging. However, the majority of previous research has focused on assessing the detection of neutral or synthetic odors, with little attention given to the impact of aging and neurodegeneration on the recognition of social cues-a critical feature for the survival of mammalian species. Therefore, in this study, we present a battery of olfactory tests that use conspecific urine samples to examine the changes in social odor recognition in a mouse model of neurodegeneration.

Topological analysis of sharp-wave ripple waveforms reveals input mechanisms behind feature variations.

The reactivation of experience-based neural activity patterns in the hippocampus is crucial for learning and memory. These reactivation patterns and their associated sharp-wave ripples (SWRs) are highly variable. However, this variability is missed by commonly used spectral methods. Here, we use topological and dimensionality reduction techniques to analyze the waveform of ripples recorded at the pyramidal layer of CA1. We show that SWR waveforms distribute along a continuum in a low-dimensional space, which conveys information about the underlying layer-specific synaptic inputs. A decoder trained in this space successfully links individual ripples with their expected sinks and sources, demonstrating how physiological mechanisms shape SWR variability. Furthermore, we found that SWR waveforms segregated differently during wakefulness and sleep before and after a series of cognitive tasks, with striking effects of novelty and learning. Our results thus highlight how the topological analysis of ripple waveforms enables a deeper physiological understanding of SWRs.

Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits.

A high percentage of patients with brain metastases frequently develop neurocognitive symptoms; however, understanding how brain metastasis co-opts the function of neuronal circuits beyond a tumor mass effect remains unknown. We report a comprehensive multidimensional modeling of brain functional analyses in the context of brain metastasis. By testing different preclinical models of brain metastasis from various primary sources and oncogenic profiles, we dissociated the heterogeneous impact on local field potential oscillatory activity from cortical and hippocampal areas that we detected from the homogeneous inter-model tumor size or glial response. In contrast, we report a potential underlying molecular program responsible for impairing neuronal crosstalk by scoring the transcriptomic and mutational profiles in a model-specific manner. Additionally, measurement of various brain activity readouts matched with machine learning strategies confirmed model-specific alterations that could help predict the presence and subtype of metastasis.

Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus.

Cognitive function relies on a balanced interplay between excitatory and inhibitory neurons (INs), but the impact of estradiol on IN function is not fully understood. Here, we characterize the regulation of hippocampal INs by aromatase, the enzyme responsible for estradiol synthesis, using a combination of molecular, genetic, functional and behavioral tools. The results show that CA1 parvalbumin-expressing INs (PV-INs) contribute to brain estradiol synthesis. Brain aromatase regulates synaptic inhibition through a mechanism that involves modification of perineuronal nets enwrapping PV-INs. In the female brain, aromatase modulates PV-INs activity, the dynamics of network oscillations and hippocampal-dependent memory. Aromatase regulation of PV-INs and inhibitory synapses is determined by the gonads and independent of sex chromosomes. These results suggest PV-INs are mediators of estrogenic regulation of behaviorally-relevant activity.

An update to Hippocampome.org by integrating single-cell phenotypes with circuit function in vivo.

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org. We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.

Development of Action Potential Waveform in Hippocampal CA1 Pyramidal Neurons.

CA1 pyramidal neurons undergo intense morphological and electrophysiological changes from the second to third postnatal weeks in rats throughout a critical period associated with the emergence of exploratory behavior. Using whole cell current-clamp recordings in vitro and neurochemical methods, we studied the development of the somatic action potential (AP) waveform and some of the underlying channels in this critical period. At the third postnatal week, APs showed a more hyperpolarized threshold, higher duration and amplitude. Subthreshold depolarization broadened APs and depolarized their peak overshoots more pronouncedly in immature neurons (2 weeks old). These features were mimicked by pharmacologically blocking the fast-inactivating A-type potassium current (IA) and matched well with the higher concentrations of Kv4.2 and Kv4.3 and the lower concentrations of BK and Kv1.2 channels detected by Western blotting. Repetitive stimulation with high frequency trains (50 Hz) reproduced AP broadening associated to inactivation of the A-type current in immature cells. Moreover, repetitive firing showed changes in AP amplitude consistent with the inactivation of both sodium and potassium subthreshold currents, which resulted in higher AP amplitudes in the more immature neurons. We propose that maturation of AP waveform and excitability in this critical developmental period could be related to the onset of exploratory behaviors.

Proximodistal Organization of the CA2 Hippocampal Area.

The proximodistal axis is considered a major organizational principle of the hippocampus. At the interface between the hippocampus and other brain structures, CA2 apparently breaks this rule. The region is involved in social, temporal, and contextual memory function, but mechanisms remain elusive. Here, we reveal cell-type heterogeneity and a characteristic expression gradient of the transcription factor Sox5 within CA2 in the rat. Using intracellular and extracellular recordings followed by neurochemical identification of single cells, we find marked proximodistal trends of synaptic activity, subthreshold membrane potentials, and phase-locked firing coupled to theta and gamma oscillations. Phase-shifting membrane potentials and opposite proximodistal correlations with theta sinks and sources at different layers support influences from different current generators. CA2 oscillatory activity and place coding of rats running in a linear maze reflect proximodistal state-dependent trends. We suggest that the structure and function of CA2 are distributed along the proximodistal hippocampal axis.

Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican.

Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function.

Role of low-voltage-activated calcium current and extracellular calcium in controlling the firing pattern of developing CA1 pyramidal neurons.

The firing pattern of individual neurons is an important element for information processing and storing. During the first weeks of development, there is a transitional period during which CA1 pyramidal neurons display burst-spiking behavior in contrast to the adult regular-firing pattern. Spike after-depolarizations (ADPs) constitute a major factor underlying burst-spiking behavior. Using current-clamp recordings, we studied ADP waveforms and firing patterns in CA1 pyramidal neurons of Wistar rats from 9 to 19 postnatal days (P9-19). The percentage of burst-spiking neurons increased up to P16, in correlation with the emergence of an active component in the ADP. The application of low-voltage-activated (LVA) calcium channel blockers such as nickel or mibefradil suppressed the generation of the active ADP component and burst-spiking behavior. In agreement with the development of the ADP waveform and burst-spiking behavior, voltage-clamp experiments in dissociated pyramidal neurons showed an increase in the LVA calcium current in P16-19 vs P9-12. Finally, we found that a reduction of extracellular calcium levels decreases the percentage of burst-spiking cells due to a reduction in the active component of the ADP. We conclude that a major contribution of LVA calcium channels to ADP determines the bursting capability of CA1 pyramidal neurons during a transitional postnatal period in contrast to adulthood.

Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples.

Sharp-wave ripples represent a prominent synchronous activity pattern in the mammalian hippocampus during sleep and immobility. GABAergic interneuronal types are silenced or fire during these events, but the mechanism of pyramidal cell (PC) participation remains elusive. We found opposite membrane polarization of deep (closer to stratum oriens) and superficial (closer to stratum radiatum) rat CA1 PCs during sharp-wave ripples. Using sharp and multi-site recordings in combination with neurochemical profiling, we observed a predominant inhibitory drive of deep calbindin (CB)-immunonegative PCs that contrasts with a prominent depolarization of superficial CB-immunopositive PCs. Biased contribution of perisomatic GABAergic inputs, together with suppression of CA2 PCs, may explain the selection of CA1 PCs during sharp-wave ripples. A deep-superficial gradient interacted with behavioral and spatial effects to determine cell participation during sleep and awake sharp-wave ripples in freely moving rats. Thus, the firing dynamics of hippocampal PCs are exquisitely controlled at subcellular and microcircuit levels in a cell type-selective manner.

Simplest relationship between local field potential and intracellular signals in layered neural tissue.

The relationship between the extracellularly measured electric field potential resulting from synaptic activity in an ensemble of neurons and intracellular signals in these neurons is an important but still open question. Based on a model neuron with a cylindrical dendrite and lumped soma, we derive a formula that substantiates a proportionality between the local field potential and the total somatic transmembrane current that emerges from the difference between the somatic and dendritic membrane potentials. The formula is tested by intra- and extracellular recordings of evoked synaptic responses in hippocampal slices. Additionally, the contribution of different membrane currents to the field potential is demonstrated in a two-population mean-field model. Our formalism, which allows for a simple estimation of unknown dendritic currents directly from somatic measurements, provides an interpretation of the local field potential in terms of intracellularly measurable synaptic signals. It is also applicable to the study of cortical activity using two-compartment neuronal population models.