Dendrites have always fascinated researchers: from the artistic drawings by Ramon y Cajal to the beautiful recordings of today, neuroscientists have been striving to unravel the mysteries of these structures. Theoretical work in the 1960s predicted important dendritic effects on neuronal processing, establishing computational modelling as a powerful technique for their investigation. Since then, modelling of dendrites has been instrumental in driving neuroscience research in a targeted manner, providing experimentally testable predictions that range from the subcellular level to the systems level, and their relevance extends to fields beyond neuroscience, such as machine learning and artificial intelligence. Validation of modelling predictions often requires - and drives - new technological advances, thus closing the loop with theory-driven experimentation that moves the field forward. This Review features the most important, to our understanding, contributions of modelling of dendritic computations, including those pending experimental verification, and highlights studies of successful interactions between the modelling and experimental neuroscience communities.

Illuminating dendritic function with computational models.

Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural signals during unrestrained behavior and their open-source versions have made them affordable. Often, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight miniscope with a small footprint that integrates a high-sensitivity image sensor, an inertial measurement unit and an LED driver for an external optogenetic probe. We use it to perform the first concurrent cellular resolution recordings from cerebellum and cerebral cortex in unrestrained mice, demonstrate its optogenetic stimulation capabilities to examine cerebello-cerebral or cortico-striatal connectivity, and replicate findings of action encoding in dorsal striatum. In combination with cross-platform acquisition and control software, our miniscope is a versatile addition to the expanding tool chest of open-source miniscopes that will increase access to multi-region circuit investigations during unrestrained behavior.

/pdf/ninscope-a-versatile-miniscope-for-multi-region-circuit-4ropau6zhm.pdf

NINscope, a versatile miniscope for multi-region circuit investigations.

While memories are often thought of as flashbacks to a previous experience, they do not simply conserve veridical representations of the past but must continually integrate new information to ensure survival in dynamic environments. Therefore, 'drift' in neural firing patterns, typically construed as disruptive 'instability' or an undesirable consequence of noise, may actually be useful for updating memories. In our view, continual modifications in memory representations reconcile classical theories of stable memory traces with neural drift. Here we review how memory representations are updated through dynamic recruitment of neuronal ensembles on the basis of excitability and functional connectivity at the time of learning. Overall, we emphasize the importance of considering memories not as static entities, but instead as flexible network states that reactivate and evolve across time and experience.

The brain in motion: How ensemble fluidity drives memory-updating and flexibility.

Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural activity during unrestrained behavior and their open-source versions have helped to distribute them at an affordable cost. Generally, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight, small footprint open-source miniscope that incorporates a high-sensitivity image sensor, an inertial measurement unit (IMU), and an LED driver for an external optogenetic probe. We highlight the advantages of NINscope by performing the first simultaneous cellular resolution (dual scope) recordings from cerebellum and cerebral cortex in unrestrained mice, revealing that the activity of both regions generally precede the onset of behavioral acceleration. At the same time, we demonstrate the optogenetic stimulation capabilities of NINscope and show that cerebral cortical activity can be driven strongly by cerebellar stimulation. Finally, we combine optogenetic stimulation of cortex with imaging in the dorsal striatum and replicate previous studies that show action space is encoded by neurons in this subcortical region. In combination with cross-platform control software NINscope is a versatile addition to the expanding toolbox of open-source miniscopes and will aid multi-region circuit investigations during unrestrained behavior.

https://www.biorxiv.org/content/biorxiv/early/2019/07/05/685909.full.pdf

NINscope: a versatile miniscope for multi-region circuit investigations

People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology.

Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer's Disease.

Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.

/pdf/breakdown-of-spatial-coding-and-interneuron-synchronization-5gecdandom.pdf

Breakdown of spatial coding and interneuron synchronization in epileptic mice.

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Breakdown of spatial coding and interneuron synchronization in epileptic mice.