LFP publications

Integration of multi-frequency sounds into a unified perceptual object is critical for recognizing syllables in speech. This “feature binding” relies on the precise synchrony of each component’s onset timing, but little is known regarding its neural correlates. We find that multi-frequency sounds prevalent in vocalizations, specifically harmonics, preferentially activate the mouse secondary auditory cortex (A2), whose response deteriorates with shifts in component onset timings. The temporal window for harmonics integration in A2 was broadened by inactivation of somatostatin-expressing interneurons (SOM cells), but not parvalbumin-expressing interneurons (PV cells). Importantly, A2 has functionally connected subnetworks of neurons preferentially encoding harmonic over inharmonic sounds. These subnetworks are stable across days and exist prior to experimental harmonics exposure, suggesting their formation during development. Furthermore, A2 inactivation impairs performance in a discrimination task for coincident harmonics. Together, we propose A2 as a locus for multi-frequency integration, which may form the circuit basis for vocal processing.

Here we report the pharmacologic blockade of voltage-gated sodium ion channels (Na V s) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of Na V s to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of Na V s. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to Na V -dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial Na V block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca 2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca 2+ -permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca 2+ -impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro , and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC 50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

Perceptual organization in mice depends on feedback from higher visual areas, with specific roles for VIP and SOM interneurons.

The representation of space in mouse visual cortex was thought to be relatively uniform. Here we reveal, using population receptive-field (pRF) mapping techniques, that mouse visual cortex contains a region in which pRFs are considerably smaller. This region, the “focea,” represents a location in space in front of, and slightly above, the mouse. Using two-photon imaging we show that the smaller pRFs are due to lower scatter of receptive-fields at the focea and an over-representation of binocular regions of space. We show that receptive-fields of single-neurons in areas LM and AL are smaller at the focea and that mice have improved visual resolution in this region of space. Furthermore, freely moving mice make compensatory eye-movements to hold this region in front of them. Our results indicate that mice have spatial biases in their visual processing, a finding that has important implications for the use of the mouse model of vision.

Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.

Significance Humans and animals recognize light tactile stimulations on some occasions while at others miss even stronger stimuli. The explanation of this apparent paradox lies in the competition between spontaneously and externally evoked responses in the brain. Brief bursts of beta-oscillations have been implicated in reduced detection rates, yet the underlying mechanism remained unknown. Here, we report that neural networks exhibit synchronization during beta-bursts, followed by reduced firing rates, thus explaining the diminished detection rate on the single trial level. Through monitoring the brain’s electrical activity before and during tactile stimulation, we found that the masking influence of burst occupancy on perception can be counterbalanced in real time by adjusting the stimulus intensity, thereby overcoming this active inhibition of sensory cortex.

A dopaminergic neural circuit projecting from the VTA to the hindbrain regulates feeding by transducing meal satiation signals.

Background Cerebellar electrical stimulation has shown promise in improving motor recovery post-stroke in both rodent and human studies. Past studies have used motor evoked potentials (MEPs) to evaluate how cerebellar stimulation modulates ongoing activity in the cortex, but the underlying mechanisms are incompletely understood. Here we used invasive electrophysiological recordings from the intact and stroke-injured rodent primary motor cortex (M1) to assess how epidural cerebellar stimulation modulates neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics. Methods We recorded single unit spiking and local field potentials (LFPs) in both the intact and acutely stroke-injured M1 contralateral to the stimulated cerebellum in adult Long-Evans rats under anesthesia. We analyzed changes in the firing rates of single units, the extent of synchronous spiking and power spectral density (PSD) changes in LFPs during and post-stimulation. Results Our results show that post-stimulation, the firing rates of a majority of M1 neurons changed significantly with respect to their baseline rates. These firing rate changes were diverse in character, as the firing rate of some neurons increased while others decreased. Additionally, these changes started to set in during stimulation. Furthermore, cross-correlation analysis showed a significant increase in coincident firing amongst neuronal pairs. Interestingly, this increase in synchrony was unrelated to the direction of firing rate change. We also found that neuronal ensembles derived through principal component analysis were more active post-stimulation. Lastly, these changes occurred without a significant change in the overall spectral power of LFPs post-stimulation. Conclusions Our results show that cerebellar stimulation caused significant, long-lasting changes in the activity patterns of M1 neurons by altering firing rates, boosting neural synchrony and increasing neuronal assemblies’ activation strength. Our study provides evidence that cerebellar stimulation can directly modulate cortical dynamics. Since these results are present in the perilesional cortex, our data might also help explain the facilitatory effects of cerebellar stimulation post-stroke.

The mechanisms that govern thalamocortical transmission are poorly understood. Recent data have shown that sensory stimuli elicit activity in ensembles of cortical neurons that recapitulate stereotyped spontaneous activity patterns. Here, we elucidate a possible mechanism by which gating of patterned population cortical activity occurs. In this study, sensory-evoked all-or-none cortical population responses were observed in the mouse auditory cortex in vivo and similar stochastic cortical responses were observed in a colliculo-thalamocortical brain slice preparation. Cortical responses were associated with decreases in auditory thalamic synaptic inhibition and increases in thalamic synchrony. Silencing of corticothalamic neurons in layer 6 (but not layer 5) or the thalamic reticular nucleus linearized the cortical responses, suggesting that layer 6 corticothalamic feedback via the thalamic reticular nucleus was responsible for gating stochastic cortical population responses. These data implicate a corticothalamic-thalamic reticular nucleus circuit that modifies thalamic neuronal synchronization to recruit populations of cortical neurons for sensory representations.

Aggregation and self-sorting of cells in three dimensional cultures have been described for non-neuronal cells. Despite increased interest in engineered neural tissues for treating brain injury or for modeling neurological disorders in vitro, little data is available on collective cell movements in neuronal aggregates. Migration and sorting of cells may alter these constructs’ morphology and, therefore, the function of their neural circuitry. In this work, linear, adhered rat and human 3D neuronal-astrocyte cultures were developed to enable the study of aggregation and sorting of these cells. An in silico model of the contraction, clustering, and cell sorting in the 3D cultures was also developed. Experiments and computational modeling showed that aggregation was mainly a neuron mediated process, and formation of astrocyte-rich sheaths in 3D cultures depended on differential attraction between neurons and astrocytes. In silico model predicted formation of self-assembled neuronal layers in disk-shaped 3D cultures. Neuronal activity patterns were found to correlate with local morphological differences. This model of neuronal and astrocyte aggregation and sorting may benefit future design of neuronal constructs.

Hair cells detect sound, head position or water movements when their mechanosensory hair bundle is deflected. Each hair bundle has an asymmetric architecture that restricts stimulus detection to a single axis. Coordinated hair cell orientations within sensory epithelia further tune stimulus detection at the organ level. Here, we identify GPR156, an orphan GPCR of unknown function, as a critical regulator of hair cell orientation. We demonstrate that the transcription factor EMX2 polarizes GPR156 distribution, enabling it to signal through Gαi and trigger a 180° reversal in hair cell orientation. GPR156-Gαi mediated reversal is essential to establish hair cells with mirror-image orientations in mouse otolith organs in the vestibular system and in zebrafish lateral line. Remarkably, GPR156-Gαi also instructs hair cell reversal in the auditory epithelium, despite a lack of mirror-image organization. Overall, our work demonstrates that conserved GPR156-Gαi signaling is integral to the framework that builds directional responses into mechanosensory epithelia.

Objective. The electrode–tissue interface surrounding a deep brain stimulation (DBS) lead is known to be highly dynamic following implantation, which may have implications on the interpretation of intraoperatively recorded local field potentials (LFPs). We characterized beta-band LFP dynamics following implantation of a directional DBS lead in the sensorimotor subthalamic nucleus (STN), which is a primary target for treating Parkinson’s disease. Approach. Directional STN-DBS leads were implanted in four healthy, non-human primates. LFPs were recorded over two weeks and again 1–4 months after implantation. Impedance was measured for two weeks post-implant without stimulation to compare the reactive tissue response to changes in LFP oscillations. Beta-band (12–30 Hz) peak power was calculated from the LFP power spectra using both common average referencing (CAR) and intra-row bipolar referencing (IRBR). Results. Resting-state LFPs in two of four subjects revealed a steady increase of beta power over the initial two weeks post-implant whereas the other two subjects showed variable changes over time. Beta power variance across days was significantly larger in the first two weeks compared to 1–4 months post-implant in all three long-term subjects. Further, spatial maps of beta power several hours after implantation did not correlate with those measured two weeks or 1–4 months post-implant. CAR and IRBR beta power correlated across short- and long-term time points. However, depending on the time period, subjects showed a significant bias towards larger beta power using one referencing scheme over the other. Lastly, electrode–tissue impedance increased over the two weeks post-implant but showed no significant correlation to beta power. Significance. These results suggest that beta power in the STN may undergo significant changes following DBS lead implantation. DBS lead diameter and electrode recording configurations can affect the post-implant interpretation of oscillatory features. Such insights will be important for extrapolating results from intraoperative and externalized LFP recordings.

Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique, but its mechanisms remain unclear. We hypothesize that if tFUS parameters exhibit distinct modulation effects in different neuron populations, then the mechanism can be understood through identifying unique features in these neuron populations. In this work, we investigate the effect of tFUS stimulation on different functional neuron types in in vivo anesthetized rodent brains. Single neuron recordings were separated into regular-spiking and fast-spiking units based on their extracellular spike shapes acquired through intracranial electrophysiological recordings, and further validated in transgenic optogenetic mice models of light-excitable excitatory and inhibitory neurons. We show that excitatory and inhibitory neurons are intrinsically different in response to ultrasound pulse repetition frequency (PRF). The results suggest that we can preferentially target specific neuron types noninvasively by tuning the tFUS PRF. Chemically deafened rats and genetically deafened mice were further tested for validating the directly local neural effects induced by tFUS without potential auditory confounds.

Background: Auditory hallucinations (which occur when the distinction between thoughts and perceptions is blurred) are common in psychotic disorders. The orbitofrontal cortex (OFC) may be implicated, because it receives multiple inputs, including sound and affective value via the amygdala, orchestrating complex emotional responses. We aimed to elucidate the circuit and neuromodulatory mechanisms that underlie the processing of emotionally salient auditory stimuli in the OFC — mechanisms that may be involved in auditory hallucinations. Methods: We identified the cortico-cortical connectivity conveying auditory information to the mouse OFC; its sensitivity to neuromodulators involved in psychosis and postpartum depression, such as dopamine and neurosteroids; and its sensitivity to sensory gating (defective in dysexecutive syndromes). Results: Retrograde tracers in OFC revealed input cells in all auditory cortices. Acoustic responses were abolished by pharmacological and chemogenetic inactivation of the above-identified pathway. Acoustic responses in the OFC were reduced by local dopaminergic agonists and neurosteroids. Noticeably, apomorphine action lasted longer in the OFC than in auditory areas, and its effect was modality-specific (augmentation for visual responses), whereas neurosteroid action was sex-specific. Finally, acoustic responses in the OFC reverberated to the auditory association cortex via feedback connections and displayed sensory gating, a phenomenon of local origin, given that it was not detectable in input auditory cortices. Limitations: Although our findings were for mice, connectivity and sensitivity to neuromodulation are conserved across mammals. Conclusion: The corticocortical loop from the auditory association cortex to the OFC is dramatically sensitive to dopamine and neurosteroids. This suggests a clinically testable circuit behind auditory hallucinations. The function of OFC input–output circuits can be studied in mice with targeted and clinically relevant mutations related to their response to emotionally salient sounds.

Working memory (WM), the ability to actively hold information in memory over a delay period of seconds, is a fundamental constituent of cognition. Delay-period activity in sensory cortices has been observed in WM tasks, but whether and when the activity plays a functional role for memory maintenance remains unclear. Here, we investigated the causal role of auditory cortex (AC) for memory maintenance in mice performing an auditory WM task. Electrophysiological recordings revealed that AC neurons were active not only during the presentation of the auditory stimulus but also early in the delay period. Furthermore, optogenetic suppression of neural activity in AC during the stimulus epoch and early delay period impaired WM performance, whereas suppression later in the delay period did not. Thus, AC is essential for information encoding and maintenance in auditory WM task, especially during the early delay period.

The hippocampal local field potential (LFP) exhibits a strong correlation with behavior. During rest, the theta rhythm is not prominent, but during active behavior, there are strong rhythms in the theta, theta harmonics, and gamma ranges. With increasing running velocity, theta, theta harmonics and gamma increase in power and in cross-frequency coupling, suggesting that neural entrainment is a direct consequence of the total excitatory input. While it is common to study the parametric range between the LFP and its complementing power spectra between deep rest and epochs of high running velocity, it is also possible to explore how the spectra degrades as the energy is completely quenched from the system. Specifically, it is unknown whether the 1/f slope is preserved as synaptic activity becomes diminished, as low frequencies are generated by large pools of neurons while higher frequencies comprise the activity of more local neuronal populations. To test this hypothesis, we examined rat LFPs recorded from the hippocampus and entorhinal cortex during barbiturate overdose euthanasia. Within the hippocampus, the initial stage entailed a quasi-stationary LFP state with a power-law feature in the power spectral density. In the second stage, there was a successive erosion of power from high- to low-frequencies in the second stage that continued until the only dominant remaining power was <20 Hz. This stage was followed by a rapid collapse of power spectrum toward the absolute electrothermal noise background. As the collapse of activity occurred later in hippocampus compared with medial entorhinal cortex, it suggests that the ability of a neural network to maintain the 1/f slope with decreasing energy is a function of general connectivity. Broadly, these data support the energy cascade theory where there is a cascade of energy from large cortical populations into smaller loops, such as those that supports the higher frequency gamma rhythm. As energy is pulled from the system, neural entrainment at gamma frequency (and higher) decline first. The larger loops, comprising a larger population, are fault-tolerant to a point capable of maintaining their activity before a final collapse.

Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.

Although the neural circuitry underlying fear memory formation is important in fear-related mental disorders, it is incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. Moreover, we used the loss of function and rescue experiments to demonstrate that release of the neuropeptide cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons extend from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK-dependent signaling in the EC prevented long-term potentiation of sensory signals to the LA and formation of trace fear memory. Altogether, we suggest a model where sensory stimuli trigger the release of CCK from EC neurons, which potentiates sensory signals to the LA, ultimately influencing neural plasticity and trace fear memory formation.

Cortical spreading depolarization (CSD) is a propagating wave of tissue depolarization characterized by a large increase of extracellular potassium concentration and prolonged subsequent electrical silencing of neurons. Waves of CSD arise spontaneously in various acute neurological settings, including migraine aura and ischemic stroke. Recently, we have reported that pan-inhibition of adrenergic receptors (AdRs) facilitates the normalization of extracellular potassium after acute photothrombotic stroke in mice. Here, we have extended that mechanistic study to ask whether AdR antagonists also modify the dynamics of KCl-induced CSD and post-CSD recovery in vivo. Spontaneous neural activity and KCl-induced CSD were visualized by cortex-wide transcranial Ca 2+ imaging in G-CaMP7 transgenic mice. AdR antagonism decreased the recurrence of CSD waves and accelerated the post-CSD recovery of neural activity. Two-photon imaging revealed that astrocytes exhibited aberrant Ca 2+ signaling after passage of the CSD wave. This astrocytic Ca 2+ activity was diminished by the AdR antagonists. Furthermore, AdR pan-antagonism facilitated the normalization of the extracellular potassium level after CSD, which paralleled the recovery of neural activity. These observations add support to the proposal that neuroprotective effects of AdR pan-antagonism arise from accelerated normalization of extracellular K + levels in the setting of acute brain injury.