BrainWAVE: A flexible method for noninvasive stimulation of brain rhythms across species

Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds ( flicker ). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here, we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel open-source methods for flicker stimulation across rodents and humans. We demonstrate rapid, cross-species induction of rhythmic activity without behavioral confounds in multiple settings from electrophysiology to neuroimaging. This flicker approach provides an exceptional opportunity to discover the therapeutic effects of brain rhythms across scales and species

Gamma frequency entrainment attenuates amyloid load and modifies microglia

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)[subscript 1-40] and Aβ [subscript 1-42] isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ[subscript 1-40] and Aβ[subscript 1-42] levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.National Institutes of Health (U.S.) (Grant 1R01EY023173)National Institutes of Health (U.S.) (Grant 1DP1NS087724)National Institutes of Health (U.S.) (Grant RF1AG047661)National Institutes of Health (U.S.) (Grant ROIGM104948

Media actors' perceptions of their roles in reporting food incidents

Background: Previous research has shown that the media can play a role in shaping consumer perceptions during a public health crisis. In order for public health professionals to communicate well-informed health information to the media, it is important that they understand how media view their role in transmitting public health information to consumers and decide what information to present. This paper reports the perceptions of media actors from three countries about their role in reporting information during a food incident. This information is used to present ideas and suggestions for public health professionals working with media during food incidents. Methods: Thirty three semi-structured interviews with media actors from Australia, New Zealand and the United Kingdom were conducted and analysed thematically. Media actors were recruited via purposive sampling using a sampling strategy, from a variety of formats including newspaper, television, radio and online. Results: Media actors said that during a food incident, they play two roles. First, they play a role in communicating information to consumers by acting as a conduit for information between the public and the relevant authorities. Second, they play a role as investigators by acting as a public watchdog. Conclusion: Media actors are an important source of consumer information during food incidents. Public health professionals can work with media by actively approaching them with information about food incidents; promoting to media that as public health professionals, they are best placed to provide the facts about food incidents; and by providing angles for further investigation and directing media to relevant and correct information to inform such investigations. Public health professionals who adapt how they work with media are more likely to influence media to portray messages that fit what they would like the public to know and that are in line with public health recommendations and enable consumers to engage in safe and health promoting behaviours in response to food incidents

Decoding Memory in Health and Alzheimer’s Disease

Presented on April 9, 2019 at 8:30 a.m. in the Parker H. Petit Institute for Bioengineering and Bioscience, Room 1128.Annabelle Singer is a neuroscientist with extensive experience in the biology of learning and memory from health to disease, from animal models to humans, and from computations within neurons to across populations of cells. She is currently an Assistant Professor in George Tech’s Department of Biomedical Engineering.Runtime: 44:52 minutesIn this talk I will discuss how neural activity goes awry in Alzheimer’s disease, driving specific frequencies of neural activity recruits the brain’s immune system, and new methods to drive rhythmic activity non-invasively. Spatial navigation deficits are one of the earliest symptoms of AD and the hippocampus is one of the areas first affected by the disease. First, I will describe how neural codes underlying memory-based spatial decisions fail in animal models Alzheimer’s disease (AD). Using a virtual reality behavior paradigm to record and manipulate neural activity in transgenic mice, the primary animal model of AD, we found deficits in hippocampal neural activity early in the progression of the disease. These deficits occurred in the same patterns of activity that we have found inform memory-guided decisions in a spatial navigation task. Next, I will discuss the effects of driving these patterns of activity in AD model mice. We found that driving gamma activity, the activity lacking in AD mice, mobilized the immune system to remove pathogenic proteins. Specifically, driving gamma recruited the primary immune cells of the brain, microglia, to alter their morphology and increase engulfment of beta-amyloid. Finally, I will discuss new non-invasive methods we are developing to drive rhythmic neural activity non-invasively. Ultimately, these discoveries could lead to new therapies for Alzheimer’s disease by driving specific patterns of neural activity to impact the disease at the cognitive, cellular, and molecular levels

Hippocampal Codes in Spatial Memory and Alzheimer’s Disease

Presented on October 31, 2016 at 11:00 a.m. in the Engineered Biosystems Building (EBB), Room 1005Annabelle Singer is an Assistant Professor in the Coulter Department of Biomedical Engineering at Georgia Tech. Her research takes a multi-dimensional approach to deciphering neural activity, observing and manipulating such activity during behavior to understand how the brain learns and remembers experiences. In the course of her research Dr. Singer has developed new methods to record neural activity during behavior, novel approaches to analyze complex neural data, and new approaches to treat cognitive disease.Runtime: 48:31 minutesThe hippocampus is essential for both spatial navigation and episodic memory. While decades of research has revealed patterns of neural activity in the hippocampus that represent information about the spatial environment, called spatial coding, how these patterns relate to memory processes is still unclear. Our lab uses a combination of behavior, neural recording, optogenetic manipulation, and computational tools to understand the neural underpinning of learning and memory in health and disease. In this talk I will address how hippocampal neural codes guide memory-based decisions and how they go awry in disease’s that effect memory. First, by recording the activity of many single neurons simultaneously as an animal learns a spatial navigation task, we examined how spatial codes inform future decisions. We found that when an animal has to choose a path through space, the hippocampus reactivates neural activity that represents the possible paths to choose from, essentially foreseeing where to go based on past experience. We then examined how this activity fails in Alzheimer’s disease (AD), since spatial navigation deficits are one of the earliest symptoms of AD and the hippocampus is one of the areas first affected by the disease. Using a virtual reality behavior paradigm to record and manipulate neural activity in transgenic mice, the primary animal model of AD, we found deficits in hippocampal neural activity early in the progression of the disease. These deficits occurred in the same patterns of activity that we have found inform memory-guided decisions in a spatial navigation task. Finally, I will discuss optogenetically driving these patterns of activity in the AD mouse model

Learning, Remembering, and Relating Sequences in the Hippocampus

As a crossroads between sensory inputs and long term memories, the hippocampus turns a plethora of information into concise episodes for us to remember. The hippocampus can employ different strategies to achieve this transformation. By selecting only notable experiences to transfer to long term memory storage, we can remember important experiences while forgetting the mundane. By encoding common principles among several experiences, we can remember appropriate general responses and predict future similar experiences. We considered ways the hippocampus might achieve these two possibilities by examining hippocampal activity while rats executed sequences for rewards. Given that we must remember the experiences that lead to reward in order to exploit these rewards in the future, we asked if memory processes are enhanced by reward. In particular we examined hippocampal sharp wave-ripples (SWRs) because reactivation of previous experiences during SWRs is thought to be essential for event memory storage. We found that SWR activity increases when animals receive reward. This reward related SWR activity is further enhanced when animals have to learn new path-reward associations. Additionally, SWR activity reactivates neural patterns that occur as animals run to or from the reward. Because SWRs are implicated in memory consolidation, this enhanced SWR reactivation could be a mechanism to preferentially remember experiences associated with reward. Furthermore, when navigating environments with many repeated elements, generalizing across elements can be advantageous to efficiently encode appropriate responses. Simultaneously, each element must also be differentiated from the others. To study this, we then examined hippocampal activity as animals traversed environments with many repeated elements and had to distinguish between these elements to receive reward. We found that some hippocampal cells fire very similarly on multiple repeated elements, while other cells encode the elements differently. Cells that generalize across similar elements have correlated moment to moment activity, suggesting that they are part of functional ensembles. Furthermore, this generalizing / path equivalent activity increases as animals learn new relationships between repeated elements. This generalization across repeating elements could be a mechanism to extract general principles about related experiences

Principles of designing interpretable optogenetic behavior experiments

Over the last decade, there has been much excitement about the use of optogenetic tools to test whether specific cells, regions, and projection pathways are necessary or sufficient for initiating, sustaining, or altering behavior. However, the use of such tools can result in side effects that can complicate experimental design or interpretation. The presence of optogenetic proteins in cells, the effects of heat and light, and the activity of specific ions conducted by optogenetic proteins can result in cellular side effects. At the network level, activation or silencing of defined neural populations can alter the physiology of local or distant circuits, sometimes in undesired ways. We discuss how, in order to design interpretable behavioral experiments using optogenetics, one can understand, and control for, these potential confounds.National Institutes of Health (U.S.) (NIH Director’s Pioneer Award 1DP1NS087724)MIT Media Lab ConsortiumNational Institutes of Health (U.S.) (NIH grant 1R01DA029639)National Institutes of Health (U.S.) (NIH grant 2R44NS070453)Massachusetts Institute of Technology. Synthetic Intelligence Laborator

Hippocampal SWR Activity Predicts Correct Decisions during the Initial Learning of an Alternation Task

The hippocampus frequently replays memories of past experiences during sharp-wave ripple (SWR) events. These events can represent spatial trajectories extending from the animal's current location to distant locations, suggesting a role in the evaluation of upcoming choices. While SWRs have been linked to learning and memory, the specific role of awake replay remains unclear. Here we show that there is greater coordinated neural activity during SWRs preceding correct, as compared to incorrect, trials in a spatial alternation task. As a result, the proportion of cell pairs coactive during SWRs was predictive of subsequent correct or incorrect responses on a trial-by-trial basis. This effect was seen specifically during early learning, when the hippocampus is essential for task performance. SWR activity preceding correct trials represented multiple trajectories that included both correct and incorrect options. These results suggest that reactivation during awake SWRs contributes to the evaluation of possible choices during memory-guided decision making

Evidence for Long-Timescale Patterns of Synaptic Inputs in CA1 of Awake Behaving Mice

Repeated sequences of neural activity are a pervasive feature of neural networks in vivo and in vitro. In the hippocampus, sequential firing of many neurons over periods of 100-300 ms reoccurs during behavior and during periods of quiescence. However, it is not known whether the hippocampus produces longer sequences of activity or whether such sequences are restricted to specific network states. Furthermore, whether long repeated patterns of activity are transmitted to single cells downstream is unclear. To answer these questions, we recorded intracellularly from hippocampal CA1 of awake, behaving male mice to examine both subthreshold activity and spiking output in single neurons. In eight of nine recordings, we discovered long (900 ms) reoccurring subthreshold fluctuations or “repeats.” Repeats generally were high-amplitude, nonoscillatory events reoccurring with 10msprecision. Using statistical controls, we determined that repeats occurred more often than would be expected from unstructured network activity (e.g., by chance). Most spikes occurred during a repeat, and when a repeat contained a spike, the spike reoccurred with precision on the order of ≤ 20 ms, showing that long repeated patterns of subthreshold activity are strongly connected to spike output. Unexpectedly, we found that repeats occurred independently of classic hippocampal network states like theta oscillations or sharp-wave ripples. Together, these results reveal surprisingly long patterns of repeated activity in the hippocampal network that occur nonstochastically, are transmitted to single downstream neurons, and strongly shape their output. This suggests that the timescale of information transmission in the hippocampal network is much longer than previously thought. Keywords: hippocampus; intracellular activity; subthreshold patternsNational Institutes of Health (U.S.) (Award 1DP1-NS-087724)National Institutes of Health (U.S.) (Award 1R01-MH-103910