Viewing archives for Waddell Group
Megan Carey
Abstract: Every movement we make requires us to precisely coordinate muscle activity across our body in space and time. In this talk I will describe our efforts to understand how the brain generates flexible, coordinated movement. We have taken a behavior-centric approach to this problem, starting with the development of quantitative frameworks for mouse locomotion (LocoMouse; Machado et al., eLife 2015, 2020) and locomotor learning, in which mice adapt their locomotor symmetry in response to environmental perturbations (Darmohray et al., Neuron 2019). Combined with genetic circuit dissection, these studies reveal specific, cerebellum-dependent features of these complex, whole-body behaviors. This provides a key entry point for understanding how neural computations within the highly stereotyped cerebellar circuit support the precise coordination of muscle activity in space and time. Finally, I will present recent unpublished data that provide surprising insights into how cerebellar circuits flexibly coordinate whole-body movements in dynamic environments.
Maintaining flexible brain function when hunger dictates you should be seeking food
When we are short of energy, circulating neurohormones and modulators prime our body and brain to mobilise our remaining metabolic resources and to promote food-seeking and consummatory behaviours. Although the drive to relieve our hunger can be all encompassing, our brains retain the capacity to do other things if required.
Prior work from the Waddell group established that both hunger and thirst motivated resource seeking behaviours are under the control of the fly’s dopaminergic system (Krashes et al., 2009; Senapati et al., 2019), which is composed of about 200 neurons representing rewards and 10-fold fewer representing aversive things (Li et al., 2020). Their studies have shown that a key element of the deprivation-state specific control of the expression of food- and water-seeking memories is provided by neuropeptidergic inhibition of two particular types of aversive dopaminergic neurons (Krashes et al., 2009; Senapati et al., 2019). Using the dopaminergic system this way for motivational purpose raises the question of how the system retains the ability to signal aversion, when these neurons are inhibited to promote resource seeking.
In the new work led by postdoctoral fellow Eleonora Meschi, the group provide an answer to this question. Dr. Meschi discovered that endocrine release of the fly’s functional equivalent of glucagon, called adipokinetic hormone (AKH), compensates for the hunger-dependent suppression of aversive dopaminergic neuron activity, by facilitating the strength of input pathways that convey punitive information to these neurons.
Eleonora says, ‘The project developed from my original and completely unexpected finding that hungry flies lacking glucagon/AKH had normal food-reinforced learning but poor shock-reinforced learning. By tracking AKH signalling from the bloodstream to the brain we discovered why this was the case. AKH regulates the activity of neural pathways that relay unpleasant signals, like painful shock and bitter taste, to dopaminergic neurons that write aversive memories.’
When hungry, flies release more AKH into their circulating haemolymph. Meschi demonstrated that AKH influences aversive learning behaviour by activating four large neurons in the base of the brain that express the AKH receptor. Interestingly, the cell bodies of these neurons reside outside of the glial covering of the brain, giving them direct access to the circulatory environment, and nutrient status, of the fly’s body. Using connectomics, research technician Georgia Dempsey and postdoctoral fellow Nils Otto, mapped the neurons downstream of the AKH response neurons, which revealed 135 neurons that could be clustered into 38 distinct neuronal types. Critically, these neurons project axons that ascend from the base of the brain to the top, where many of them were found to selectively synapse onto aversively reinforcing dopaminergic neurons.
With DPhil student Lucille Duquenoy, Dr. Meschi used live-imaging of a transgenic fluorescent dopamine sensor to show that hunger increased the shock-evoked release of dopamine from the aversive dopaminergic neurons and that this facilitation required AKH signalling. Further genetic experiments established that AKH signalling directs modulation of the ascending neurons so that they more efficiently relay punitive information, such as electric shock and bitter taste, from the periphery to the aversive dopamine neurons that are required for aversive learning.
Lucille comments, ‘I have been using the new genetically-encoded GRAB dopamine sensors from Yulong Li’s group to measure stimulus-evoked dopamine release from specific neurons in the fly brain. With Eleonora, I found that electric shocks produce more dopamine release from aversive neurons if the flies are chronically hungry and that shock-triggered dopamine release was greatly reduced in flies with no AKH signalling.’
In the published paper the Waddell group note that similar mechanisms may exist in the mammalian brain, between nutrient-responsive neurons in the hypothalamus, and neurons that project from there to dopaminergic neurons in the ventral tegmental area.
Read the paper here
Julie H. Simpson
Abstract: How the nervous system coordinates complex behaviors remains a puzzle. Grooming behavior in the fruit fly Drosophila is a sequence composed of leg movements targeted to clean different body parts. Grooming is initiated by sensory cues and executed by motor circuits. There is an anterior to posterior progression based on a suppression hierarchy. The wealth of genetic tools and anatomical resources make this behavior a powerful experimental model system to explore how innate, rhythmic, but flexible sequences are controlled by neural architecture we may share. I will present new work from my lab at UCSB starting from command-like neurons to uncover principles that organize this behavior as well as the circuits that implement them. I will briefly explain how forays into the connectome motivate my UK sabbatical project to design new genetic reagents to access neurons of interest.
Bio: Julie H. Simpson received an AB from Princeton in Molecular Biology with research experience in fruit fly eye development. After a year of rice viral genetics in Costa Rica, she obtained a PhD at UC Berkeley in axon guidance at the fly embryonic midline. After a post-doc at University of Wisconsin, Madison, studying temperature sensitive ion channels and screening for neurons affecting fly motor control, she was one of the early Group Leaders at the HHMI Janelia Research Campus. Her research group used the new tools for targeting and manipulating neuronal activity with temperature and light to map circuits governing a range of behaviors. She joined UC Santa Barbara in 2015, where her lab performs genetic screens for neurons and circuits that govern fly grooming behavior.
Paul Frankland
Abstract:
Memories for events (i.e., episodic memories) formed in early development differ from those in adulthood in at least two regards. First, these memories tend to be rapidly forgotten (i.e., infantile amnesia). Second, they tend to be less precise than those formed in adulthood (i.e., infantile generalization). My talk will focus on the neurobiological mechanisms that account for these different operating characteristics of episodic memory in the developing brain. With respect to infantile amnesia, our studies have shown that maturation of hippocampal and cortical circuits is necessary for the formation of enduring event memories. With respect to infantile generalization, our studies reveal that maturation of inhibitory microcircuits in the hippocampus are necessary for the formation of adult-like, precise memories for events.
Flies neglect food and endure shocks to seek a dopamine reward
The group led by Scott Waddell, used optogenetics to activate a subset of reward-encoding dopamine neurons together with an odour. In the confocal microscopy image above, these dopaminergic neurons (in white) target the mushroom body (in blue), the centre of olfactory learning and memory in the fly brain. Prior work suggests that these dopamine neurons are highly diverse and ordinarily convey different reward types as parallel teaching signals to the mushroom body.
Using optogenetic activation, the team discovered that they could generate olfactory associations that starved flies would seek while neglecting food or enduring electric shocks. This was not observed when flies were trained to associate an odour with the activation of other neurons in the brain or with a natural reward such as sugar.
The researchers discovered that flies took risks to endure shock while seeking reward because the dopamine neurons that ordinarily signal electric shock punishment were functionally impaired by prior activation of the reward-encoding dopamine neurons. This revealed antagonism between reward-encoding and punishment-encoding dopamine neurons in the brain.
Ordinarily, reward-encoding dopamine neurons are thought to send teaching signals to the mushroom body to reinforce olfactory associative learning. However, starved flies sought sugar less even after the reward-encoding dopamine neurons were activated in the absence of odour. This suggested that the dopamine neurons also convey satiety-like ‘demotivational signals’.
Since flies ordinarily do not neglect food or endure shock to seek reward, the team reasoned that the activity of these dopamine neurons must ordinarily be tightly controlled. In the paper, the authors present physiological and anatomical evidence that this is indeed the case.
Calcium imaging of these dopamine neurons using two-photon microscopy revealed that the dopamine neurons convey signals that are specific to both reward type and the physiological state of the fly. The researchers also observed calcium responses that resembled teaching signals and satiety-like signals in these neurons.
Moreover, using the latest connectome data of the fly hemibrain, the authors found that the reward-encoding dopamine neurons (approximately 60 in total) receive inputs from over 1700 neurons from all over the brain (visualized in the connectome image below). This is over 25 times as many inputs, suggesting that these dopamine neurons have elaborate input controls.
Anatomical reconstruction (from the fly hemibrain connectome) of over 1700 upstream neurons in the fly brain which target the approximately 60 dopamine neurons that drive reward seeking despite adverse consequences. Upstream neurons are coloured according to the various brain regions from which they emanate.
With all this evidence, Professor Scott Waddell and Dr Kristijan Jovanoski propose that these heterogeneously rich reward-encoding dopamine neurons are ordinarily tightly controlled by upstream neurons that convey reward type and physiological state. Optogenetically activating these dopamine neurons bypasses their elaborate input control and destroys the reward-specificity and state-specificity of their signalling. Consequently, flies seek a non-specific reward that is greater than the sum of individual rewards, leading to supranormal reward seeking despite electric shocks or physiological needs.
Given that there are many parallels between the dopamine neurons of flies and mammals, the authors propose that the mechanisms discovered here may similarly apply towards understanding unconstrained reward-seeking behaviour and substance use disorders in mammals.
The full paper ‘Dopaminergic systems create reward seeking despite adverse consequences’ is available to read in Nature .
Multisensory learning binds neurons into a cross-modal memory engram
Scott Waddell appointed Fellow of the Royal Society
Congratulations are in order to Scott Waddell on his election to The Royal Society.
Professor Scott Waddell FMedSci FRS is DPAG’s Professor of Neurobiology and Wellcome Trust Principal Research Fellow in Basic Biomedical Science at the Centre for Neural Circuits and Behaviour. Professor Waddell discovered novel, conserved mechanisms of adaptive behaviour. His studies in Drosophila revealed an unexpected degree of specialization in the structure and function of dopaminergic circuits. Different, genetically and structurally defined, dopaminergic neurons provide valence- and even reward type-specific teaching signals. Opposing systems of positive and negative reinforcement control goal-directed memory formation and expression at discrete anatomical sites. When learned expectations are not met, the original memory remains but is updated by integration with a new memory of opposite sign at a separate location. Intelligent behaviour is therefore informed by a catalogue of parallel memories accrued over time. The most recent research from the Waddell lab published in Nature discovered a detailed neural circuit mechanism that explains how multisensory learning improves memory performance.
Professor Waddell’s has been recognised with a number of prestigious awards, including the 2014 Liliane Bettencourt Prize for the Life Sciences, the 2018 Bindra Lectures, election to The Academy of Medical Sciences in 2021, and a Wellcome Discovery Award in 2022.
Gerry Rubin
Annika Barber
Abstract: The Drosophila clock network is a network of peptidergic oscillators, with neuropeptides coordinating network activity and conveying time-of-day information to circadian output regions that regulate circadian behavior and physiology. While connectivity within the clock network is well-established, how the clock conveys time-of-day information to output regions remains unknown. Both clock neurons, and neurons within the pars intercerebralis (PI), a major circadian output hub, secrete multiple neuropeptides and small molecule neurotransmitters that may work in concert. Using clock-neuron-specific CRISPR, we have identified novel output neuropeptides that play sex-specific roles in regulating circadian rest-activity behavior. Clock neurons provide time-of-day specific signals to the PI via both neuropeptides and small molecule neurotransmitters. Further, we have identified intra-PI connectivity which allows integration of time-of-day cues with additional sensory inputs to guide appropriate behavior selection in complex environments.
Biography: Annika Barber was a Postdoctoral Research Fellow in the Department of Neuroscience at the University of Pennsylvania. In the lab of Dr. Amita Sehgal, her research focused on understanding the coordination of competing and complementary behaviors such as circadian rhythms, sleep, feeding, and mating in the pars intercerebralis, a proto-hypothalamic region in Drosophila. Annika received her Ph.D. in Cell Biology from Thomas Jefferson University and her B.S. in Biology from Bryn Athyn College.