Odors activate distributed ensembles of neurons within piriform cortex, forming cortical representations of odor thought to be essential to olfactory learning and behaviors. This odor response is driven by direct input from the olfactory bulb, but is also shaped by a dense network of associative or intracortical inputs to piriform, which may enhance or constrain the cortical odor representation. With optogenetic techniques, it is possible to functionally isolate associative inputs to piriform cortex and assess their potential to activate or inhibit piriform pyramidal neurons. The anterior olfactory nucleus (AON) receives direct input from the olfactory bulb and sends an associative projection to piriform cortex that has potential roles in the state-dependent processing of olfactory behaviors. Here, we provide a detailed functional assessment of the AON afferents to piriform in male and female C57/Bl6 mice. We confirm that the AON forms glutamatergic excitatory synapses onto piriform pyramidal neurons, and ...

Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular–tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ–tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF–tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early n...

Natural conversation is multisensory: when we can see the speaker's face, visual speech cues improve our comprehension. The neuronal mechanisms underlying this phenomenon remain unclear. The two main alternatives are visually mediated phase modulation of neuronal oscillations (excitability fluctuations) in auditory neurons and visual input-evoked responses in auditory neurons. Investigating this question using naturalistic audiovisual speech with intracranial recordings in humans of both sexes, we find evidence for both mechanisms. Remarkably, auditory cortical neurons track the temporal dynamics of purely visual speech using the phase of their slow oscillations and phase-related modulations in broadband high-frequency activity. Consistent with known perceptual enhancement effects, the visual phase reset amplifies the cortical representation of concomitant auditory speech. In contrast to this, and in line with earlier reports, visual input reduces the amplitude of evoked responses to concomitant auditory i...

Ca2+ spikes initiated in the distal trunk of layer 5 pyramidal cells (PCs) underlie nonlinear dynamic changes in the gain of cellular response, critical for top-down control of cortical processing. Detailed models with many compartments and dozens of ionic channels can account for this Ca2+ spike-dependent gain and associated critical frequency. However, current models do not account for all known Ca2+-dependent features. Previous attempts to include more features have required increasing complexity, limiting their interpretability and utility for studying large population dynamics. We overcome these limitations in a minimal two-compartment biophysical model. In our model, a basal-dendrites/somatic compartment included fast-inactivating Na+ and delayed-rectifier K+ conductances, while an apical-dendrites/trunk compartment included persistent Na+, hyperpolarization-activated cation (I h ), slow-inactivating K+, muscarinic K+, and Ca2+ L-type. The model replicated the Ca2+ spike morphology and its critical f...

The interplay between hippocampus and medial entorhinal cortex (mEC) is of key importance for forming spatial representations. Within the hippocampal–entorhinal loop, the hippocampus receives context-specific signals from layers II/III of the mEC and feeds memory-associated activity back into layer V (LV). The processing of this output signal within the mEC, however, is largely unknown. We characterized the activation of the receiving mEC network by evoked and naturally occurring output patterns in mouse hippocampal-entorhinal cortex slices. Both types of glutamatergic neurons (mEC LVa and LVb) as well as fast-spiking inhibitory interneurons receive direct excitatory input from the intermediate/ventral hippocampus. Connections between the two types of excitatory neurons are sparse, and local processing of hippocampal output signals within mEC LV is asymmetric, favoring excitation of far projecting LVa neurons over locally projecting LVb neurons. These findings suggest a new role for mEC LV as a bifurcation...

Andrei Rozov, Märt Rannap, Franziska Lorenz, Azat Nasretdinov, Andreas Draguhn, et al. (see pages [8413–8425][1]) Much of the communication between the hippocampus and the rest of the brain is transmitted through the entorhinal cortex. Neurons in entorhinal cortical layer 2 (L2) and L3 provide

Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular Ca2+ flux, and cellular biogenesis. Although the purposes of apposing mitochondria and ER have been described, an understanding of altered organelle connectomics related to disease states is emerging. Since inner ear outer hair cell (OHC) degeneration is a common trait of age-related hearing loss, the objective of this study was to investigate whether the structural and functional coupling of mitochondria with subsurface cisternae (SSC) was affected by aging. We applied functional and structural probes to equal numbers of male and female mice with a hearing phenotype akin to human aging. We discovered the polarization of cristae and crista junctions in mitochondria tethered to the SSC in OHCs. Aging was associated with SSC stress and decoupling of mitochondria with the SSC, mitochondrial fission/fusion imbalance, a remarkable red...

The role of the ventromedial prefrontal cortex (vmPFC) in human pavlovian threat conditioning has been relegated largely to the extinction or reversal of previously acquired stimulus–outcome associations. However, recent neuroimaging evidence questions this view by also showing activity in the vmPFC during threat acquisition. Here we investigate the casual role of vmPFC in the acquisition of pavlovian threat conditioning by assessing skin conductance response (SCR) and declarative memory of stimulus–outcome contingencies during a differential pavlovian threat-conditioning paradigm in eight patients with a bilateral vmPFC lesion, 10 with a lesion outside PFC and 10 healthy participants (each group included both females and males). Results showed that patients with vmPFC lesion failed to produce a conditioned SCR during threat acquisition, despite no evidence of compromised SCR to unconditioned stimulus or compromised declarative memory for stimulus–outcome contingencies. These results suggest that the vmPFC...

Precise information on synapse organization in a dendrite is crucial to understanding the mechanisms underlying voltage integration and the variability in the strength of synaptic inputs across dendrites of different complex morphologies. Here, we used focused ion beam/scanning electron microscope (FIB/SEM) to image the dendritic spines of mice in the hippocampal CA1 region, CA3 region, somatosensory cortex, striatum, and cerebellum (CB). Our results show that the spine geometry and dimensions differ across neuronal cell types. Despite this difference, dendritic spines were organized in an orchestrated manner such that the postsynaptic density (PSD) area per unit length of dendrite scaled positively with the dendritic diameter in CA1 proximal stratum radiatum (PSR), cortex and CB. The ratio of the PSD area to neck length was kept relatively uniform across dendrites of different diameters in CA1 PSR. Computer simulation suggests that a similar level of synaptic strength across different dendrites in CA1 PSR...