Faculty Bibliography

Bouts of high frequency activity known as sharp wave ripples (SPW-Rs) facilitate communication between the hippocampus and neocortex. However, the paths and mechanisms by which SPW-Rs broadcast their content are not well understood. Due to its anatomical positioning, the granular retrosplenial cortex (gRSC) may be a bridge for this hippocampo-cortical dialogue. Using silicon probe recordings in awake, head-fixed mice, we show the existence of SPW-R analogues in gRSC and demonstrate their coupling to hippocampal SPW-Rs. gRSC neurons reliably distinguished different subclasses of hippocampal SPW-Rs according to ensemble activity patterns in CA1. We demonstrate that this coupling is brain state-dependent, and delineate a topographically-organized anatomical pathway via VGlut2-expressing, bursty neurons in the subiculum. Optogenetic stimulation or inhibition of bursty subicular cells induced or reduced responses in superficial gRSC, respectively. These results identify a specific path and underlying mechanisms by which the hippocampus can convey neuronal content to the neocortex during SPW-Rs.

The mnemonic functions of hippocampal sharp wave ripples (SPW-Rs) have been studied extensively. Because hippocampal outputs affect not only cortical but also subcortical targets, we examined the impact of SPW-Rs on the firing patterns of lateral septal (LS) neurons in behaving rats. A large fraction of SPW-Rs were temporally locked to high-frequency oscillations (HFOs) (120-180 Hz) in LS, with strongest coupling during non-rapid eye movement (NREM) sleep, followed by waking immobility. However, coherence and spike-local field potential (LFP) coupling between the two structures were low, suggesting that HFOs are generated locally within the LS GABAergic population. This hypothesis was supported by optogenetic induction of HFOs in LS. Spiking of LS neurons was largely independent of the sequential order of spiking in SPW-Rs but instead correlated with the magnitude of excitatory synchrony of the hippocampal output. Thus, LS is strongly activated by SPW-Rs and may convey hippocampal population events to its hypothalamic and brainstem targets.

Spiking activity of place cells in the hippocampus encodes the animal's position as it moves through an environment. Within a cell's place field, both the firing rate and the phase of spiking in the local theta oscillation contain spatial information. We propose a position-theta-phase (PTP) model that captures the simultaneous expression of the firing-rate code and theta-phase code in place cell spiking. This model parametrically characterizes place fields to compare across cells, time, and conditions; generates realistic place cell simulation data; and conceptualizes a framework for principled hypothesis testing to identify additional features of place cell activity. We use the PTP model to assess the effect of running speed in place cell data recorded from rats running on linear tracks. For the majority of place fields, we do not find evidence for speed modulation of the firing rate. For a small subset of place fields, we find firing rates significantly increase or decrease with speed. We use the PTP model to compare candidate mechanisms of speed modulation in significantly modulated fields and determine that speed acts as a gain control on the magnitude of firing rate. Our model provides a tool that connects rigorous analysis with a computational framework for understanding place cell activity.

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.

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. Prolongation of spontaneously occurring ripples by optogenetic stimulation, but not randomly induced ripples, increased memory during maze learning. The neuronal content of randomly induced ripples was similar to short-duration spontaneous ripples and contained little spatial information. The spike content of the optogenetically prolonged ripples was biased by the ongoing, naturally initiated neuronal sequences. Prolonged ripples recruited new neurons that represented either arm of the maze. Long-duration hippocampal SPW-Rs replaying large parts of planned routes are critical for memory.

During non-rapid eye movement (NREM) sleep, neuronal populations in the mammalian forebrain alternate between periods of spiking and inactivity. Termed the slow oscillation in the neocortex and sharp wave-ripples in the hippocampus, these alternations are often considered separately but are both crucial for NREM functions. By directly comparing experimental observations of naturally-sleeping rats with a mean field model of an adapting, recurrent neuronal population, we find that the neocortical alternations reflect a dynamical regime in which a stable active state is interrupted by transient inactive states (slow waves) while the hippocampal alternations reflect a stable inactive state interrupted by transient active states (sharp waves). We propose that during NREM sleep in the rodent, hippocampal and neocortical populations are excitable: each in a stable state from which internal fluctuations or external perturbation can evoke the stereotyped population events that mediate NREM functions.

Transcutaneous electric stimulation (TES) using weak currents has been used extensively in attempts to influence brain activity. In vitro and in vivo experiments in rodents and computational modeling suggest that the magnitude of voltage gradient of the induced electric field should exceed 1 mV/mm to instantaneously and reproducibly alter neuronal spiking and consequent brain network patterns. Evidence for immediate and unconditional neuronal effects of TES in the human brain is still lacking, mainly due to the saturation of the recording amplifiers by the large induced electromagnetic fields. For many therapeutic applications, it is desirable to affect neurons in a regionally constrained manner to reach maximum on-target effects and reduce side effects on unintended brain networks. Here, we determine the needed TES currents in human cadavers to achieve 1 mV/mm fields. Scalp stimulation greatly reduced the generated intracerebral electric fields (>50% in cadavers) and these measurements predicted that ~5 mA is needed to achieve 1mV/mm electric field gradient via scalp stimulation. To reach the desired intracerebral field strength without the adverse peripheral effects of >5 mA currents, we introduce a spatially focused multiple site, Intersectional Short-Pulse (ISP) stimulation. We demonstrate the instantaneous entraining effect of ISP on alpha waves in human subjects and on neuronal spiking in rats. Immediate effects of TES can be best utilized in disorders with sudden, major electrographic changes such as epileptic seizures. We showed earlier that thalamocortical seizures can be quickly terminated by temporally targeted, diffuse transcranial stimulation, however secondarily generalized temporal lobe seizures are more resistant to these diffuse interference interventions. ISP also has the capacity to spatially focus its effect, thus it is capable to overcome the unwanted mirror effect (anodal vs cathodal) of the traditional TES protocols. We report here a novel stimulation pattern, that can simultaneously entrain both hippocampi. To evaluate its utility, temporal lobe seizures were induced in rats by electrical kindling, and each electrically kindled seizures were automatically detected and silenced by a closed loop ISP stimulation. By comparing to closed-loop diffuse TES, we found that ISP with bilateral foci is more effective in early seizure termination. Lastly, we introduce our prototyping efforts to implement an implantable, minimal-invasive, transcranial closed-loop seizure termination device, aiming for human clinical applications.

The relationship between mesoscopic local field potentials (LFPs) and single-neuron firing in the multi-layered neocortex is poorly understood. Simultaneous recordings from all layers in the primary visual cortex (V1) of the behaving mouse revealed functionally defined layers in V1. The depth of maximum spike power and sink-source distributions of LFPs provided consistent laminar landmarks across animals. Coherence of gamma oscillations (30-100 Hz) and spike-LFP coupling identified six physiological layers and further sublayers. Firing rates, burstiness, and other electrophysiological features of neurons displayed unique layer and brain state dependence. Spike transmission strength from layer 2/3 cells to layer 5 pyramidal cells and interneurons was stronger during waking compared with non-REM sleep but stronger during non-REM sleep among deep-layer excitatory neurons. A subset of deep-layer neurons was active exclusively in the DOWN state of non-REM sleep. These results bridge mesoscopic LFPs and single-neuron interactions with laminar structure in V1.

Slow-oscillations and spindle activity during non-REM sleep have been implicated in memory consolidation. Closed-loop acoustic stimulation has previously been shown to enhance slow oscillations and spindle activity during sleep and improve verbal associative memory. We assessed the effect of closed-loop acoustic stimulation during a daytime nap on a virtual reality spatial navigation task in 12 healthy human subjects in a randomized within-subject crossover design. We show robust enhancement of slow-spindle activity during sleep. However, no effects on behavioral performance were observed when comparing real versus sham stimulation. To explore whether memory enhancement effects were task-specific and dependent on nocturnal sleep, in a second experiment with 19 healthy subjects, we aimed to replicate a previous study which used closed-loop acoustic stimulation to enhance memory for word pairs. Methods were as close as possible to the original study, except we used a double-blind protocol, in which both subject and experimenter were unaware of the test condition. Again, we successfully enhanced slow-spindle power, but again did not strengthen associative memory performance with stimulation. We conclude that enhancement of slow-spindle oscillations may be insufficient to enhance memory performance in spatial navigation or verbal association tasks, and provide possible explanations for lack of behavioral replication.SIGNIFICANCE STATEMENT Prior studies have demonstrated that a closed-loop acoustic pulse paradigm during sleep can enhance verbal memory performance. This technique has widespread scientific and clinical appeal due to its non-invasive nature and ease of application. We tested with a rigorous double-blind design whether this technique could enhance key sleep rhythms associated sleep-dependent memory performance. We discovered that we could reliably enhance slow and spindle rhythms, but did not improve memory performance in the stimulation condition compared to sham condition. Our findings suggest that enhancing slow-spindle rhythms is insufficient to enhance sleep-dependent learning.