Single Unit publications

Hippocampal theta and gamma rhythms are hypothesized to play a role in the physiology of higher cognition. Prior research has reported that an offset in theta cycles between the entorhinal cortex, CA3, and CA1 regions promotes independence of population activity across the hippocampus. In line with this idea, it has recently been observed that CA1 pyramidal cells can establish and maintain coordinated place cell activity intrinsically, with minimal reliance on afferent input. Counter to these observations is the contemporary hypothesis that CA1 neuron activity is driven by a gamma oscillation arising from the medial entorhinal cortex (MEC) that relays information by providing precisely timed synchrony between MEC and CA1. Reinvestigating this in rats during appetitive track running, we found that theta is the dominant frequency of cross-frequency coupling between the MEC and hippocampus, with hippocampal gamma largely independent of entorhinal gamma.

Theta oscillations are a hallmark of hippocampal activity across mammals and play a critical role in many hippocampal models of memory and spatial navigation. To reconcile the cross-species differences observed in the presence and properties of theta, we recorded hippocampal local field potentials in rats and ferrets during auditory and visual localisation tasks designed to vary locomotion and sensory attention. Here, we show that theta oscillations occur during locomotion in both ferrets and rats, however during periods of immobility, theta oscillations persist in the ferret, contrasting starkly with the switch to large irregular activity (LIA) in the rat. Theta during immobility in the ferret is identified as analogous to Type 2 theta that has been observed in rodents due to its sensitivity to atropine, and is modulated by behavioural state with the strongest theta observed during reward epochs. These results demonstrate that even under similar behavioural conditions, differences exist between species in the relationship between theta and behavioural state.

Humans and other primates recognize one another in part based on unique structural details of the face, including both local features and their spatial configuration within the head and body. Visual analysis of the face is supported by specialized regions of the primate cerebral cortex, which in macaques are commonly known as face patches. Here we ask whether the responses of neurons in anterior face patches, thought to encode face identity, are more strongly driven by local or holistic facial structure. We created stimuli consisting of recombinant photorealistic images of macaques, where we interchanged the eyes, mouth, head, and body between individuals. Unexpectedly, neurons in the anterior medial (AM) and anterior fundus (AF) face patches were predominantly tuned to local facial features, with minimal neural selectivity for feature combinations. These findings indicate that the high-level structural encoding of face identity rests upon populations of neurons specialized for local features.

The brain is a highly organized, dynamic system whose network architecture is often assessed through resting functional magnetic resonance imaging (fMRI) functional connectivity. The functional interactions between brain areas, including those observed during rest, are assumed to stem from the collective influence of action potentials carried by long-range neural projections. However, the contribution of individual neurons to brain-wide functional connectivity has not been systematically assessed. Here we developed a method to concurrently measure and compare the spiking activity of local neurons with fMRI signals measured across the brain during rest. We recorded spontaneous activity from neural populations in cortical face patches in the macaque during fMRI scanning sessions. Individual cells exhibited prominent, bilateral coupling with fMRI fluctuations in a restricted set of cortical areas inside and outside the face patch network, partially matching the pattern of known anatomical projections. Within each face patch population, a subset of neurons was positively coupled with the face patch network and another was negatively coupled. The same cells showed inverse correlations with distinct subcortical structures, most notably the lateral geniculate nucleus and brainstem neuromodulatory centers. Corresponding connectivity maps derived from fMRI seeds and local field potentials differed from the single unit maps, particularly in subcortical areas. Together, the results demonstrate that the spiking fluctuations of neurons are selectively coupled with discrete brain regions, with the coupling governed in part by anatomical network connections and in part by indirect neuromodulatory pathways.

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes, including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history dependence of these "offset" responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single-unit activity from primary AC. We identified parvalbumin and somatostatin interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence, but not the dynamics, of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type-specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli.SIGNIFICANCE STATEMENT Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is used along this separate, "offset" information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogeneous, and show no cell type-specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions.

Neural activity exhibits oscillations, bursts, and resonance, enhancing responsiveness at preferential frequencies. For example, theta-frequency bursting and resonance in granule cells facilitate synaptic transmission and plasticity mechanisms at the input stage of the cerebellar cortex. However, whether theta-frequency bursting of Purkinje cells is involved in generating rhythmic behavior has remained neglected. We recorded and optogenetically modulated the simple and complex spike activity of Purkinje cells while monitoring whisker movements with a high-speed camera of awake, head-fixed mice. During spontaneous whisking, both simple spike activity and whisker movement exhibit peaks within the theta band. Eliciting either simple or complex spikes at frequencies ranging from 0.5 to 28 Hz, we found that 8 Hz is the preferred frequency around which the largest movement is induced. Interestingly, oscillatory whisker movements at 8 Hz were also generated when simple spike bursting was induced at 2 and 4 Hz, but never via climbing fiber stimulation. These results indicate that 8 Hz is the resonant frequency at which the cerebellar-whisker circuitry produces rhythmic whisking.

Chronic Levodopa therapy, the gold-standard treatment for Parkinson’s Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effects of cerebellar stimulation. Moreover, cerebellar stimulation reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide motor network, and may be valuable for LID treatment.

Elevated neural plasticity during development contributes to dramatic improvements in perceptual, motor, and cognitive skills. However, malleable neural circuits are vulnerable to environmental influences that may disrupt behavioral maturation. While these risks are well-established prior to sexual maturity (i.e., critical periods), the degree of neural vulnerability during adolescence remains uncertain. Here, we induce transient hearing loss (HL) spanning adolescence in gerbils, and ask whether behavioral and neural maturation are disrupted. We find that adolescent HL causes a significant perceptual deficit that can be attributed to degraded auditory cortex processing, as assessed with wireless single neuron recordings and within-session population-level analyses. Finally, auditory cortex brain slices from adolescent HL animals reveal synaptic deficits that are distinct from those typically observed after critical period deprivation. Taken together, these results show that diminished adolescent sensory experience can cause long-lasting behavioral deficits that originate, in part, from a dysfunctional cortical circuit.

Animals can capitalize on invariance in the environment by learning and automating highly consistent actions; however, they must also remain flexible and adapt to environmental changes. It remains unclear how primary motor cortex (M1) can drive precise movements, yet also support behavioral exploration when faced with consistent errors. Using a reach-to-grasp task in rats, along with simultaneous electrophysiological monitoring in M1 and dorsolateral striatum (DLS), we find that behavioral exploration to overcome consistent task errors is closely associated with tandem increases in M1 and DLS neural variability; subsequently, consistent ensemble patterning returns with convergence to a new successful strategy. We also show that compared to reliably patterned intracranial microstimulation in M1, variable stimulation patterns result in significantly greater movement variability. Our results thus indicate that motor and striatal areas can flexibly transition between two modes, reliable neural pattern generation for automatic and precise movements versus variable neural patterning for behavioral exploration.

Animals are constantly bombarded with stimuli, which presents a fundamental problem of sorting among pervasive uninformative stimuli and novel, possibly meaningful stimuli. We evaluated novelty detection behaviorally in honey bees as they position their antennae differentially in an air stream carrying familiar or novel odors. We then characterized neuronal responses to familiar and novel odors in the first synaptic integration center in the brain–the antennal lobes. We found that the neurons that exhibited stronger initial responses to the odor that was to be familiarized are the same units that later distinguish familiar and novel odors, independently of chemical identities. These units, including both tentative projection neurons and local neurons, showed a decreased response to the familiar odor but an increased response to the novel odor. Our results suggest that the antennal lobe may represent familiarity or novelty to an odor stimulus in addition to its chemical identity code. Therefore, the mechanisms for novelty detection may be present in early sensory processing, either as a result of local synaptic interaction or via feedback from higher brain centers.

Spinal interneurons play a critical role in motor output. A given interneuron may receive convergent input from several different sensory modalities and descending centers and relay this information to just as many targets. Therefore, there is a critical need to quantify populations of spinal interneurons simultaneously. Here, we quantify the functional connectivity of spinal neurons through the concurrent recording of populations of lumbar interneurons and hindlimb motor units in the in vivo cat model during activation of either the ipsilateral sural nerve or contralateral tibial nerve. Two microelectrode arrays were placed into lamina VII, one at L3 and a second at L6/7, while an electrode array was placed on the surface of the exposed muscle. Stimulation of tibial and sural nerves elicited similar changes in the discharge rate of both interneurons and motor units. However, these same neurons showed highly significant differences in prevalence and magnitude of correlated activity underlying these two forms of afferent drive. Activation of the ipsilateral sural nerve resulted in highly correlated activity, particularly at the caudal array. In contrast, the contralateral tibial nerve resulted in less, but more widespread correlated activity at both arrays. These data suggest that the ipsilateral sural nerve has dense projections onto caudal lumbar spinal neurons, while contralateral tibial nerve has a sparse pattern of projections.

Over the last 15 years, optogenetics has changed fundamental research in neuroscience and is now reaching toward therapeutic applications. Vision restoration strategies using optogenetics are now at the forefront of these new clinical opportunities. But applications to human patients suffering from retinal diseases leading to blindness raise important concerns on the long-term functional expression of optogenes and the efficient signal transmission to higher visual centers. Here, we demonstrate in non-human primates continued expression and functionality at the retina level ∼20 months after delivery of our construct. We also performed in vivo recordings of visually evoked potentials in the primary visual cortex of anesthetized animals. Using synaptic blockers, we isolated the in vivo cortical activation resulting from the direct optogenetic stimulation of primate retina. In conclusion, our work indicates long-term transgene expression and transmission of the signal generated in the macaque retina to the visual cortex, two important features for future clinical applications.

Background To localize sound sources accurately in a reverberant environment, human binaural hearing strongly favors analyzing the initial wave front of sounds. Behavioral studies of this “precedence effect” have so far largely been confined to human subjects, limiting the scope of complementary physiological approaches. Similarly, physiological studies have mostly looked at neural responses in the inferior colliculus, the main relay point between the inner ear and the auditory cortex, or used modeling of cochlear auditory transduction in an attempt to identify likely underlying mechanisms. Studies capable of providing a direct comparison of neural coding and behavioral measures of sound localization under the precedence effect are lacking. Results We adapted a “temporal weighting function” paradigm previously developed to quantify the precedence effect in human for use in laboratory rats. The animals learned to lateralize click trains in which each click in the train had a different interaural time difference. Computing the “perceptual weight” of each click in the train revealed a strong onset bias, very similar to that reported for humans. Follow-on electrocorticographic recording experiments revealed that onset weighting of interaural time differences is a robust feature of the cortical population response, but interestingly, it often fails to manifest at individual cortical recording sites. Conclusion While previous studies suggested that the precedence effect may be caused by early processing mechanisms in the cochlea or inhibitory circuitry in the brainstem and midbrain, our results indicate that the precedence effect is not fully developed at the level of individual recording sites in the auditory cortex, but robust and consistent precedence effects are observable only in the auditory cortex at the level of cortical population responses. This indicates that the precedence effect emerges at later cortical processing stages and is a significantly “higher order” feature than has hitherto been assumed.

Objective. Extracellular microelectrode techniques are the most widely used approach to interrogate neuronal populations. However, regardless of the manufacturing method used, damage to the vasculature and circuit function during probe insertion remains a concern. This issue can be mitigated by minimising the footprint of the probe used. Reducing the size of probes typically requires either a reduction in the number of channels present in the probe, or a reduction in the individual channel area. Both lead to less effective coupling between the probe and extracellular signals of interest. Approach. Here, we show that continuously drawn SiO 2 -insulated ultra-microelectrode fibres offer an attractive substrate to address these challenges. Individual fibres can be fabricated to >10 m continuous stretches and a selection of diameters below 30 µ m with low resistance (<100 Ω mm −1 ) continuously conductive metal core of <10 µ m and atomically flat smooth shank surfaces. To optimize the properties of the miniaturised electrode-tissue interface, we electrodeposit rough Au structures followed by ∼20 nm IrOx film resulting in the reduction of the interfacial impedance to <500 kΩ at 1 kHz. Main results . We demonstrate that these ultra-low impedance electrodes can record and stimulate both single and multi-unit activity with minimal tissue disturbance and exceptional signal-to-noise ratio in both superficial (∼40 µ m) and deep (∼6 mm) structures of the mouse brain. Further, we show that sensor modifications are stable and probe manufacturing is reproducible. Significance. Minimally perturbing bidirectional neural interfacing can reveal circuit function in the mammalian brain in vivo.

Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the neural circuitry giving rise to these signals remains unknown because the functional architecture of cortical columns producing attention-associated electric fields has not been explored. Here, we detail the laminar cortical circuitry underlying an attention-associated electric field measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Last, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field that can be measured extracortically with the relative contribution of each column depending upon the underlying functional architecture.

We report on the ensemble organization of interneuronal activity in the spinal cord during locomotor movements and show that lumbar intermediate zone interneurons organize in two groups related to the two major phases of walking: stance and swing. Ensemble organization is also shown to better correlate with muscular output than single-cell activity, although ensemble membership does not appear to be somatotopically organized within the spinal cord.

Previous psychophysical studies have identified a hierarchy of time-averaged statistics which determine the identity of natural sound textures. However, it is unclear whether the neurons in the inferior colliculus (IC) are sensitive to each of these statistical features in the natural sound textures. We used 13 representative sound textures spanning the space of 3 statistics extracted from over 200 natural textures. The synthetic textures were generated by incorporating the statistical features in a step-by-step manner, in which a particular statistical feature was changed while the other statistical features remain unchanged. The extracellular activity in response to the synthetic texture stimuli was recorded in the IC of anesthetized rats. Analysis of the transient and sustained multiunit activity after each transition of statistical feature showed that the IC units were sensitive to the changes of all types of statistics, although to a varying extent. For example, we found that more neurons were sensitive to the changes in variance than that in the modulation correlations. Our results suggest that the sensitivity of the statistical features in the subcortical levels contributes to the identification and discrimination of natural sound textures.

When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here, we show in awake macaque area V1 that both repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects show some persistence on the timescale of minutes. Gamma increases are specific to the presented stimulus location. Further, repetition effects on gamma and on firing rates generalize to images of natural objects. These findings support the notion that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters.

After a briefly presented visual stimulus disappears, observers retain a detailed representation of this stimulus for a short period of time. This sensory storage is called iconic memory. We measured iconic memory in the perception of monkeys and its neuronal correlates in the primary visual cortex (area V1). We determined how many milliseconds extra viewing time iconic memory is worth and how it decays by varying the duration of a brief stimulus and the timing of a mask. The V1 activity that persists after the disappearance of a stimulus predicted accuracy, with a time course resembling the worth and decay of iconic memory. Finally, we examined how iconic memory interacts with attention. A cue presented after the stimulus disappears boosts attentional influences pertaining to a relevant part of the stimulus but only if it appears before iconic memory decayed. Our results relate iconic memory to neuronal activity in early visual cortex.

Brain injuries cause hemodynamic changes in several distant, spared areas from the lesion. Our objective was to better understand the neuronal correlates of this reorganization in awake, behaving female monkeys. We used reversible inactivation techniques to “injure” the primary motor cortex, while continuously recording neuronal activity of the ventral premotor cortex in the two hemispheres, before and after the onset of behavioral impairments. Inactivation rapidly induced profound alterations of neuronal discharges that were heterogeneous within each and across the two hemispheres, occurred during movements of either the affected or nonaffected arm, and varied during different phases of grasping. Our results support that extensive, and much more complex than expected, neuronal reorganization takes place in spared areas of the bihemispheric cortical network involved in the control of hand movements. This broad pattern of reorganization offers potential targets that should be considered for the development of neuromodulation protocols applied early after brain injury. SIGNIFICANCE STATEMENT It is well known that brain injuries cause changes in several distant, spared areas of the network, often in the premotor cortex. This reorganization is greater early after the injury and the magnitude of early changes correlates with impairments. However, studies to date have used noninvasive brain imaging approaches or have been conducted in sedated animals. Therefore, we do not know how brain injuries specifically affect the activity of neurons during the generation of movements. Our study clearly shows how a lesion rapidly impacts neurons in the premotor cortex of both hemispheres. A better understanding of these complex changes can help formulate hypotheses for the development of new treatments that specifically target neuronal reorganization induced by lesions in the brain.