The adult dentate gyrus continually produces new neurons that integrate into the hippocampal circuit. Adult-born neurons transiently exhibit distinct cellular properties that distinguish them from the larger population of mature neurons, and these properties are thought to underlie the vital role of neurogenesis in hippocampal behaviors. I will review the developmental trajectory of adult-born neuron cellular properties and present new data focused on cellular mechanisms of “critical periods” for plasticity and information processing. The results support the idea that neurogenesis provides a substrate for experience-dependent circuit plasticity and memory precision.
The neural retina is a key organ for vision and visual processing. As a direct extension of the brain, it emerges as a prominent site impacted by Alzheimer’s disease (AD). The retina is the only CNS tissue not shielded by bone that can be easily accessible for noninvasive, affordable, ultra-high-resolution imaging in the clinical setting. Data from recent years strongly suggest it can serve as a window to assess AD. Early studies described retinal nerve fiber layer and ganglion cell degeneration. Our team revealed the accumulation of core AD hallmarks—amyloid β-protein (Aβ) plaques and neurofibrillary tangles—in the retina of AD and mild cognitive impairment (MCI) patients. Subsequent studies confirmed these findings, and further reported visual and electroretinography abnormalities, retinal tauopathy, Aβ oligomers, inflammation, and cell-specific degeneration in AD patients. Data from our group and others suggest that the brain and retina follow a similar trajectory during AD progression, potentially due to their shared embryonic origin and anatomical proximity. Moreover, retinal vascular irregularities—vessel density and fractal dimensions, blood flow, foveal avascular zone, curvature tortuosity, arteriole-to-venule ratio—are present in AD patients, including early-stage cases. A tight association between cerebral and retinal vasculopathy to cognitive deficits was reported in AD patients and animal models. More recently, we identified early and progressive retinal vascular platelet-derived growth factor receptor-β (PDGFRβ) deficiency and pericyte loss, as well as retinal endothelial tight junction losses in MCI and AD patients. These retinal vasculopathies strongly link to vascular amyloid accumulation as well as could predict the severity of cerebral amyloid angiopathy. Currently, we explore the complex landscape of Alzheimer’s in the retina, including AD-related molecular signatures and processes, new forms of proteinopathies, vascular and inflammatory abnormalities, synaptic loss, as well as cell-specific vulnerability and resilience. Establishing how early retinal biomarkers can be detected during AD continuum and what do they mean for brain pathology and functional decline, should guide the development of future retinal imaging technologies to improve early, noninvasive AD diagnosis and monitoring.
Dr. Khokhar will talk about the behavioural and neural correlates of various types of vulnerabilities to cannabis, starting from genetic risk for cannabis use, to vaping in adolescence, to the recent increases in edible overdoses in children and pets.
Vocalizations are an essential medium for social and sexual signaling in mammals and birds. Whereas most animals only produce innate vocalizations, songbirds learn to sing in a process with many parallels to human speech learning. I will discuss recent advances from our lab highlighting the neural mechanisms that enable birdsong learning, including basal ganglia-dependent vocal exploration and reinforcement. How the learned song is integrated with innate vocalizations will also be considered, with reference to recent studies that genetically map neural circuits for innate vocalizations in mice.
The DNA of every cell in our body contains the genes inherited from our parents and plays a crucial role in health and disease. While changes in the DNA itself are linked to monogenic diseases, they often fail to explain complex disorders such as neurodegenerative diseases. This can potentially be explained by additional layers of gene regulation known to be stored “above” the DNA, at the epigenetic level. Over the last years, this relatively young research field has shown that molecular structures packaging DNA in the cell nucleus influence gene activity. The DNA itself as well as its packaging structure, the so-called chromatin, can be chemically modified in many ways and is highly dynamic. With these findings, chromatin appears to be a central interface between genes and the environment, and the development and progression of diseases could be decisively influenced by epigenetic changes. Our research group investigates which epigenetic modifications are associated with complex neurological diseases – in particular Parkinson’s and Huntington’s – and how environmental factors and aging have modulating effects on them. Here, I will give an overview of current projects and highlight key findings of our work.
Creating stable memories is critical for survival. An animal relies on past learning to navigate its environment, avoid dangerous situations, and find needed resources. Because the environment is dynamic, stable memories must be updated with new information to enable responses to changing threats (a specific danger) and rewards (such as food and water). The brain circuits involved in memory and learning require both stability and flexibility. Using in vivo calcium imaging and chemogenetics, we demonstrate how new information is updated with past memories through co-reactivation of memory ensembles during offline periods including sleep.
A hidden repertoire is a functional configuration in the brain that supports behaviour but is seldom used. As a complex system, the brain can show a broad range of configurations for the same function. This “many-to-one” property imparts our brain with resilience during normal operations but also in the face of adverse events, such as damage or disease. I will cover the evidence for these repertoires and cover strategies for investigation, and the implication for the I will also relate the existence of such repertoires to variations in the qualia of our experience.
OCTOBER 27 – THIS TALK HAS BEEN CANCELLED
One of the most interesting, and mysterious, aspects of biological brains is that they form representations of environments that are richer than an interlinked series of associations, and more ‘conceptual’ than partitions in a multidimensional representation of the sensory input. Our best intuition about how this happens is that brains have evolved to pick up on, and exploit, the ubiquity of structure in the natural world and in the types of tasks that animals might have to solve over their life span, efficiently forming structured relational models of the animal’s world that can be used for planning and action. But even with that intuition, we know little about how structured knowledge is acquired or updated, especially when the extraction of the relevant structure must happen incidentally, without explicit instruction or feedback. We describe an experimental framework using rat as a model system, where the relationship between the incidentally acquired structured knowledge and the neural activity is strong enough that we can begin to decode it with confidence on single trials. Going forward, this puts us in a position to probe how structured knowledge about the world is acquired by the brain, and how it is updated with experience.
The cerebellum contains the majority of neurons in the brain and has been implicated with many aspects of motor control. In birds this includes the control of flight. In this talk, by synthesizing behavioral, neurophysiological, neuroanatomical and paleontological data I will emphasize three points: (i) the expansion of the cerebellum in birds is associated with the evolution of powered flight; (ii) retinal-recipient nuclei that analyze optic flow are critical for controlling flight; and (iii) three different visuomotor areas of the cerebellum are involved in controlling different aspects of flight.
The nucleus accumbens integrates diverse inputs, balancing threat and reward to orchestrate motivated behaviour. Glutamatergic projections from the ventral hippocampus and medial prefrontal cortex converge in the accumbens medial shell and are implicated in reward processing as well as adaptation to chronic stress. How these pathways integrate aversive or appetitive events to modulate behaviour is not fully understood and largely unstudied in females, despite known sex-differences in stress-related psychopathologies. I will present new data using pathway-specific in vivo fibre-photometry and chemogenetic silencing to uncover how these projections encode aversive experiences to shape behavioural responding to threat and integrate information about the outcome of actions to shape learning about reward.
The Fipke Integrated Neuroimaging Suite (FINS) hosts state-of-the-art neuroimaging equipment including a 3T Philips MRI scanner and a 3T GE PET/MR scanner. Our translational research includes developing better imaging tools for disorders such as multiple sclerosis, Parkinson’s, Alzheimer’s, stroke, traumatic brain injury and mental health, as well as healthy aging. This presentation will discuss many of our novel imaging techniques, including myelin water imaging, how and why they are used and what up and coming developments are available.
In this seminar I will focus on our recent studies on the role of the subthalamic nucleus in motor control and its dysregulation in movement disorders. We found that 1) subthalamic locomotor encoding and gait are highly dysregulated in Q175 Huntington’s disease (HD) mice 2) analogous gait deficits could be generated in wild type mice through optogenetic manipulation of subthalamic activity 3) subthalamic locomotor encoding and gait could be rescued in HD mice through suppression of subthalamic mutant huntingtin expression. Together, these findings argue that subthalamic activity normally optimizes movement, whereas dysregulated subthalamic activity contributes to gait deficits in HD and is a potential target for therapeutic intervention.
What is the neural basis of abstraction? Working in collaboration with experimental groups who have trained monkeys and humans on a decision task, we analyze how subjects make use of visual information and feedback to infer a hidden rule, where the rule switches in an uncued fashion. We fit a suite of behavioral models and learn that while humans are close to optimal Bayesian agents, monkey behavior is better fit as reinforcement learning, with a novel additional factor included. We use this behavioral model to elucidate structure in neural activity recorded from 200 sites across the brain, finding low-dimensional and dynamic representations of stimulus, feedback and reward prediction error that support the notion of internal states captured by the behavioral model.
Dopamine is famously involved in reward, but exactly how continues to be the subject of debate. Two key functions include signaling reward expectations to promote motivated, effortful work, and signaling errors in reward expectation to promote learning. I will present new studies from my laboratory examining each of these processes. We combine recent technological advances for measuring dopamine with novel behavioral tasks, to probe how animals compute reward expectations over multiple temporal and spatial scales.