Studying hypothalamic control of hippocampal physiology. Also interested in the networks underlying seizures and how the endocannabinoid system controls their activity.
Current Research and Scholarly Interests
I aim to better understand hippocampal network function in both physiology and epilepsy using in vivo imaging, optogenetics, and electrophysiology. I am currently addressing two main research questions: (1) what is the neurobiological basis of postictal amnesia? and (2) why do certain seizures spread to cause convulsions and others remain focal?
A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (46): e2206828119
Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.
View details for DOI 10.1073/pnas.2206828119
View details for PubMedID 36343238
A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.
2022; 13 (1): 6000
Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.
View details for DOI 10.1038/s41467-022-33536-x
View details for PubMedID 36224194
Ripple-selective GABAergic projection cells in the hippocampus.
Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the in vivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.
View details for DOI 10.1016/j.neuron.2022.04.002
View details for PubMedID 35489331
A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo.
Endocannabinoids (eCBs) are retrograde neuromodulators with important functions in a wide range of physiological processes, but their in vivo dynamics remain largely uncharacterized. Here we developed a genetically encoded eCB sensor called GRABeCB2.0. GRABeCB2.0 consists of a circular-permutated EGFP and the human CB1 cannabinoid receptor, providing cell membrane trafficking, second-resolution kinetics with high specificity for eCBs, and shows a robust fluorescence response at physiological eCB concentrations. Using GRABeCB2.0, we monitored evoked and spontaneous changes in eCB dynamics in cultured neurons and acute brain slices. We observed spontaneous compartmentalized eCB transients in cultured neurons and eCB transients from single axonal boutons in acute brain slices, suggesting constrained, localized eCB signaling. When GRABeCB2.0 was expressed in the mouse brain, we observed foot shock-elicited and running-triggered eCB signaling in the basolateral amygdala and hippocampus, respectively. In a mouse model of epilepsy, we observed a spreading wave of eCB release that followed a Ca2+ wave through the hippocampus. GRABeCB2.0 is a robust probe for eCB release in vivo.
View details for DOI 10.1038/s41587-021-01074-4
View details for PubMedID 34764491
Invivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity.
2021; 109 (15): 2398
The brain's endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling invivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling invivo.
View details for DOI 10.1016/j.neuron.2021.05.026
View details for PubMedID 34352214
Alternating sources of perisomatic inhibition during behavior.
Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally precise and millisecond-scale inhibitory regulation of neuronal ensembles delivered by PV interneurons is well established, the invivo recruitment patterns of CCK-expressing basket cell (BC) populations has remained unknown. We show in the CA1 of the mouse hippocampus that the activity of CCK BCs inversely scales with both PV and pyramidal cell activity at the behaviorally relevant timescales of seconds. Intervention experiments indicated that the inverse coupling of CCK and PV GABAergic systems arises through a mechanism involving powerful inhibitory control of CCK BCs by PV cells. The tightly coupled complementarity of two key microcircuit regulatory modules demonstrates a novel form of brain-state-specific segregation of inhibition during spontaneous behavior.
View details for DOI 10.1016/j.neuron.2021.01.003
View details for PubMedID 33529646
Supramammillary regulation of locomotion and hippocampal activity.
Science (New York, N.Y.)
2021; 374 (6574): 1492-1496
[Figure: see text].
View details for DOI 10.1126/science.abh4272
View details for PubMedID 34914519
In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia.
2020; 10 (1): 14992
Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.
View details for DOI 10.1038/s41598-020-71935-6
View details for PubMedID 32929133
Quantitative T2 MRI is predictive of neurodegeneration following organophosphate exposure in a rat model.
2020; 10 (1): 13007
Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative T2 MRI could be used as a biomarker of neurodegeneration. Quantitative T2 MRI was performed using a 9.4T MRI on rats prior to and following soman exposure. T2 images were taken at least 24h prior, 1h and 18-24h after soman exposure. Rats were pre- and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18-24h after soman exposure, significant increases in T2, a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4ms; 18-24h: 82.3 ± 13.4ms). Fluoro-Jade C staining showed significant neurodegeneration 18-24h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r=0.96, p<0.001). These findings indicate there is regionally specific neurodegeneration 24h after exposure to soman. The high correlation between T2 relaxivity and histopathology supports the use of T2 as a marker of injury.
View details for DOI 10.1038/s41598-020-69991-z
View details for PubMedID 32747689
Dynamic oxygen changes during status epilepticus and subsequent endogenous kindling
2020; 61 (7): 1515-1527
Brain tissue oxygen (partial oxygen pressure [pO2 ]) levels are tightly regulated to stay within the normoxic zone, with deviations on either side resulting in impaired brain function. Whereas pathological events such as ischemic attacks and brief seizures have previously been shown to result in pO2 levels well below the normoxic zone, oxygen levels during prolonged status epilepticus (SE) and the subsequent endogenous kindling period are unknown.We utilized two models of acquired temporal lobe epilepsy in rats: intrahippocampal kainic acid infusion and prolonged perforant pathway stimulation. Local tissue oxygen was measured in the dorsal hippocampus using an optode during and for several weeks following SE.We observed hyperoxia in the hippocampus during induced SE in both models. Following termination of SE, 88% of rats initiated focal self-generated spiking activity in the hippocampus within the first 7 days, which was associated with dynamic oxygen changes. Self-generated and recurring epileptiform activity subsequently organized into higher-frequency bursts that became progressively longer and were ultimately associated with behavioral seizures that became more severe with time and led to postictal hypoxia.Induced SE and self-generated recurrent epileptiform activity can have profound and opposing effects on brain tissue oxygenation that may serve as a biomarker for ongoing pathological activity in the brain.
View details for DOI 10.1111/epi.16554
View details for Web of Science ID 000536665200001
View details for PubMedID 32478859
View details for PubMedCentralID PMC7496277
Resolving the Micro-Macro Disconnect to Address Core Features of Seizure Networks
2019; 101 (6): 1016–28
View details for DOI 10.1016/j.neuron.2019.01.043
View details for Web of Science ID 000461901500007
- Fast oxygen dynamics as a potential biomarker for epilepsy Scientific Reports 2018: 1-7
Plants come to mind: Phytocannabinoids, endocannabinoids, and the control of seizures
View details for DOI 10.1111/add.14540
View details for PubMedCentralID PMC6597308
Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction.
2017; 58 (9): 1493-1501
A recent article by Farrell et al. characterizes the phenomenon, mechanisms, and treatment of a local and severe hypoperfusion/hypoxia event that occurs in brain regions following a focal seizure. Given the well-established role of cerebral ischemia/hypoxia in brain damage and behavioral dysfunction in other clinical settings (e.g., stroke, cerebral vasospasm), we put forward a new theory: postictal hypoperfusion/hypoxia is responsible for the negative consequences associated with seizures. Fortunately, inhibition of two separate molecular targets, cyclooxygenase-2 (COX-2) and l-type calcium channels, can prevent the expression of postictal hypoperfusion/hypoxia. These inhibitors are important experimental tools used to separate the seizure from the resulting hypoperfusion/hypoxia and can allow researchers to address the contribution of this phenomenon to negative outcomes associated with seizures. Herein we address the implications of this postictal stroke-like event in acute behavioral dysfunction (e.g., Todd's paresis) and sudden unexpected death in epilepsy (SUDEP). Moreover, anatomic alterations such as increased blood-brain barrier permeability, glial activation, central inflammation, and neuronal loss could also be a consequence of repeated hypoperfusion/hypoxic events and, in turn, underlie chronic interictal cognitive and behavioral comorbidities (e.g., memory deficits, anxiety, depression, and psychosis) and exacerbate epileptogenesis. Thus these seemingly disparate and clinically important observations may share a common point of origin: postictal hypoperfusion/hypoxia.
View details for DOI 10.1111/epi.13827
View details for PubMedID 28632329
Neurodegeneration and Pathology in Epilepsy: Clinical and Basic Perspectives.
Advances in neurobiology
2017; 15: 317-334
Epilepsy is commonly associated with a number of neurodegenerative and pathological alterations in those areas of the brain that are involved in repeated electrographic seizures. These most prominently include neuron loss and an increase in astrocyte number and size but may also include enhanced blood-brain barrier permeability, the formation of new capillaries, axonal sprouting, and central inflammation. In animal models in which seizures are either repeatedly elicited or are self-generated, a similar set of neurodegenerative and pathological alterations in brain anatomy are observed. The primary causal agent responsible for these alterations may be the cascade of events that follow a seizure and lead to an hypoperfusion/hypoxic episode. While epilepsy has long and correctly been considered an electrical disorder, the vascular system likely plays an important causal role in the neurodegeneration and pathology that occur as a consequence of repeated seizures.
View details for DOI 10.1007/978-3-319-57193-5_12
View details for PubMedID 28674987
HCN channels segregate stimulation-evoked movement responses in neocortex and allow for coordinated forelimb movements in rodents
JOURNAL OF PHYSIOLOGY-LONDON
2017; 595 (1): 247-263
The present study tested whether HCN channels contribute to the organization of motor cortex and to skilled motor behaviour during a forelimb reaching task. Experimental reductions in HCN channel signalling increase the representation of complex multiple forelimb movements in motor cortex as assessed by intracortical microstimulation. Global HCN1KO mice exhibit reduced reaching accuracy and atypical movements during a single-pellet reaching task relative to wild-type controls. Acute pharmacological inhibition of HCN channels in forelimb motor cortex decreases reaching accuracy and increases atypical movements during forelimb reaching.The mechanisms by which distinct movements of a forelimb are generated from the same area of motor cortex have remained elusive. Here we examined a role for HCN channels, given their ability to alter synaptic integration, in the expression of forelimb movement responses during intracortical microstimulation (ICMS) and movements of the forelimb on a skilled reaching task. We used short-duration high-resolution ICMS to evoke forelimb movements following pharmacological (ZD7288), experimental (electrically induced cortical seizures) or genetic approaches that we confirmed with whole-cell patch clamp to substantially reduce Ih current. We observed significant increases in the number of multiple movement responses evoked at single sites in motor maps to all three experimental manipulations in rats or mice. Global HCN1 knockout mice were less successful and exhibited atypical movements on a skilled-motor learning task relative to wild-type controls. Furthermore, in reaching-proficient rats, reaching accuracy was reduced and forelimb movements were altered during infusion of ZD7288 within motor cortex. Thus, HCN channels play a critical role in the separation of overlapping movement responses and allow for successful reaching behaviours. These data provide a novel mechanism for the encoding of multiple movement responses within shared networks of motor cortex. This mechanism supports a viewpoint of primary motor cortex as a site of dynamic integration for behavioural output.
View details for DOI 10.1113/JP273068
View details for Web of Science ID 000392021800020
View details for PubMedID 27568501
View details for PubMedCentralID PMC5199725
Postictal behavioural impairments are due to a severe prolonged hypoperfusion/ hypoxia event that is COX-2 dependent
Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable.
View details for DOI 10.7554/eLife.19352
View details for Web of Science ID 000390850800001
View details for PubMedID 27874832
View details for PubMedCentralID PMC5154758
- Epilepsy The International Encyclopedia of Social and Behavioral Sciences Oxford: Elsevier. 2015; 2nd