Dopamine Receptor D2 Hippocampal Neurons Regulate Food Intake

Post by Amanda McFarlan

What's the science?

There are a multitude of neuronal populations throughout the brain that have been identified for having a role in controlling appetite, however, it is still not known how these brain regions integrate information from past experiences and the environment to regulate feeding behaviours. The authors hypothesized that the hippocampus may be important for the integration of this information since it is well established as a brain structure that is important for spatial location and memory formation. Further, more recently, it’s its dysfunction has been shown to alter food intake. This week in the Neuron, Azevedo and colleagues investigated the role of the hippocampus is regulating food-related behaviours.

How did they do it?

The authors expressed either an inhibitory (hM4Di) or excitatory (hM3Dq) designer receptor exclusively activated by designer drugs (DREADD) in glutamatergic cells in the dorsal hippocampus of wild type mice. They activated either the inhibitory or excitatory DREADDs by infusion of clozapine-N-oxide (CNO) and observed changes in food intake over a 24-hour period. Next, the authors used PhosphoTrap (which can profile gene expression based on changes in neuronal activation) to measure hippocampal gene expression in fasted mice that underwent a behavioural task where food was presented in a context-specific manner. Next, the authors investigated the role of hippocampal dopamine receptor D2 (Drd2) neurons in food intake by performing bilateral injections of a virus containing either a Cre-dependent inhibitory or excitatory DREADD in the dentate gyrus (region of the hippocampus) in Drd2-Cre mice. They activated the inhibitory and excitatory DREADDs with infusion of CNO and measured food intake acutely (24Hr) and chronically (8 days). Then, they used multiple viral constructs (anterograde and retrograde tracers) to identify synaptic inputs onto hippocampal Drd2 neurons as well as synaptic outputs from hippocampal Drd2 neurons. Next, they targeted Channelrhodopsin-2 (a light-gated cation channel) to glutamatergic neurons in the lateral entorhinal cortex (which projects to hippocampal Drd2 neurons) and implanted optical fibers above the lateral entorhinal cortex terminals in the dentate gyrus (where Drd2 neurons are located). Similarly, they targeted the expression of either Channelrhodopsin-2 or Archaerhodopsin (an inhibitory light-gated ion channel) to hippocampal Drd2 neurons and implanted optical fibers above neuronal terminals located in the septal area. Finally, they measured changes in food intake in response to activation of synaptic inputs onto hippocampal Drd2 neurons or activation/inhibition of synaptic outputs from hippocampal Drd2 neurons.

What did they find?

The authors found that chemogenetic inhibition of hippocampal neurons increased food intake over a 24-hour period, while chemogenetic activation of hippocampal neurons decreased food intake. These data suggest that the dorsal hippocampus contains a population of glutamatergic neurons that are involved in regulating food intake in mice. Next, the authors determined that fasted mice presented with food showed significant enrichment of Drd2 in neurons located in the dentate gyrus compared to mice that were not presented with food, suggesting that hippocampal Drd2 neurons may be involved in food-related behaviours. The authors determined that in fasted mice, both acute and chronic inhibition of Drd2 hippocampal neurons increased food intake, while acute and chronic activation of these neurons decreased food intake. Together, these findings suggest that Drd2 in the hippocampus is important for regulating food intake. The authors found that Drd2 hippocampal neurons receive inputs from neurons in the superficial and middle layers of the lateral entorhinal cortex and send projections to the septal area (medial and lateral septum). Finally, they determined that optical activation of neurons in the lateral entorhinal cortex (projecting to hippocampal Drd2 neurons) and hippocampal neurons (project to septal area) decreased food intake in fasted mice, while optical inhibition of hippocampal Drd2 neurons increased food intake in fed mice. Altogether, these findings suggest that the activation of the lateral entorhinal cortex-hippocampal Drd2 pathway plays an important role in suppressing food intake.

What's the impact?

This is the first study to identify that food cues increase the neuronal activity of hippocampal Drd2 neurons. Additionally, the authors revealed that hippocampal Drd2 neurons receive inputs from the lateral entorhinal cortex and send projections to the septal area, forming a circuit that is important for regulating the suppression of food intake. Together, these findings provide a better understanding of the brain circuitry that is critical for mediating food-related behaviours.

Azevedo et al. A Role of Drd2 Hippocampal Neurons in Context-Dependent Food Intake. Neuron (2019). Access the original scientific publication here.

Brain Stimulation Using Light and Sound Reduces Alzheimer’s Pathology and Improves Cognition

Post by Deborah Joye

What's the science?

Alzheimer’s disease is a progressive form of dementia characterized by build-up of amyloid-beta (Aβ) protein plaques between nerve cells and tau protein ‘tangles’ inside of cells. Treatment options are limited, but promising research shows that neural activity can be manipulated to reduce Alzheimer’s pathology. Specifically, Alzheimer’s patients show a reduction in fast electrical ripples throughout the brain called gamma waves. Gamma waves can be induced non-invasively using a light programmed to flicker at a frequency of 40 Hz (gamma entrainment using sensory stimuli or GENUS). Exposure to the flickering light can produce gamma waves in the primary visual cortex, but it also reduces aggregates of Aβ protein, and activates microglia (the brain’s defense cells) to get rid of Aβ protein. But can GENUS be induced by other sensory systems? And can GENUS improve cognition in a model of Alzheimer’s disease? This week in Cell, Martorell and colleagues demonstrate that GENUS can be induced through both auditory and visual stimuli, reduce pathological Aβ and tau proteins, impact brain regions beyond primary sensory regions, and improve cognitive function in a mouse model of Alzheimer’s disease.

How did they do it?

The authors first checked to ensure that GENUS could be induced using an auditory tone by exposing mice to trains of tones repeating at various frequencies while simultaneously recording neural activity in the auditory cortex, hippocampus, and prefrontal cortex. To test whether auditory GENUS could improve recognition and spatial memory in a mouse model of Alzheimer’s disease, the authors employed several behavioral tasks that test hippocampus-dependent memory function: the novel object location and novel object recognition tests, which probe memory for identity or placement of an object, and the Morris Water Maze, which tests spatial memory for the location of a hidden platform. To investigate how GENUS might alter various Alzheimer’s-related proteins and cell-specific characteristics, the authors used immunohistochemistry to label Aβ and tau proteins, as well as other proteins involved with changes to astrocytes and microglia.

What did they find?

The authors found that exposure to a 40 Hz auditory tone induced GENUS in the auditory cortex, hippocampus, and prefrontal cortex. Critically, mice exposed to auditory GENUS performed better than control mice in three distinct hippocampal-dependent memory tasks, suggesting that GENUS can boost hippocampal function. Auditory GENUS also reduced the amount of Aβ protein and the pathological spreading of tau in the auditory cortex and hippocampus. Similar to effects of visual GENUS, auditory GENUS activated microglia, which increased in size and took up more Aβ. Finally, auditory GENUS increased the number of astrocytes, widened blood vessels, and increased a protein which helps to clear Aβ from the brain. When the two types of GENUS were combined, the authors found that microglia clustered around Aβ plaques, generally a precursor to phagocytosis and pathogen removal. Interestingly, auditory plus visual GENUS also reduced amyloid pathology throughout the neocortex, suggesting that inducing gamma oscillations with multiple sensory modalities can result in widespread reduction in Aβ throughout the brain.

What's the impact?

This study is the first to show that gamma waves can be induced in regions of the brain using trains of auditory tones. This study builds on previous work, demonstrating that GENUS can be induced using both auditory and visual stimuli. The authors show that auditory GENUS can improve hippocampus-dependent cognitive function in a mouse model of Alzheimer’s pathology, suggesting that GENUS could be used as a non-invasive treatment to improve cognition in Alzheimer’s patients. This research demonstrates that both auditory and visual GENUS can be used to decrease AD pathology, and that multi-sensory GENUS results in unique microglial responses to Aβ protein plaques that might increase their removal from the brain. 

Martorell et al., Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition. Cell (2019). Access the original scientific publication here.

Locomotion Changes How Neurons are Coupled to Distributed Networks

Post by Stephanie Williams

What's the science?

Computations in the brain often occur at the network level. How individual neurons participate in these computations, and how they are coupled to local (neurons nearby) and distal (neurons located further away) dynamics is still under investigation. This week in Nature Neuroscience, Clancy and colleagues investigated how the coupling of neurons to local and distant networks can dynamically change across different behavioral states.

How did they do it?                                 

The authors measured activity patterns in different brain regions of 25 mice while the mice exhibited different behaviors (eg. staying still vs. running on a wheel). The authors used different techniques to measure the activity of neurons, including electrophysiological recordings, two-photon imaging and a technique called wide-field calcium imaging. Calcium imaging relies on recording fluorescent signals emitted from neurons. When neurons spike, calcium flows into cells, activating a calcium-sensitive fluorescent protein and causing it to glow brighter. The authors recorded spiking in several regions, including: (1) visual cortex (specifically, a region called V1) and (2) retrosplenial cortex, a region known to be involved in spatial navigation. To record spiking activity from individual units, the authors inserted silicon probes into visual and retrosplenial brain areas of mice. Then, they simultaneously imaged activity across dorsal cortex using wide-field calcium imaging. They analyzed how the activity in faraway brain regions were related to the single units they were recording. The authors used the relationship between the single units and distal regions to create correlation maps of individual units with different brain areas. A major mystery of cortical activity is how variable cortical neurons are — some neurons seem to do things very differently from their neighbours. The authors investigated whether the activity of neurons that didn't seem to follow the spiking of their neighbours was more likely to be correlated with distant brain areas, which would suggest they might be directly driven by long-range projections. The authors examined how behavioral state (e.g. locomotion) impacted the activity of the neurons they recorded, and how it changed the way that individual neurons were coupled to activity in local and distal regions.

What did they find?

The authors found that many neurons showed activity similar to other neurons in the same area. However, some neurons went against this pattern and were correlated with activity in distal regions. When mice switched from quietly sitting to running on a wheel, the authors found that the coupling patterns of neurons to local and distal regions dynamically changed. They found that the firing of neurons in the visual brain area called V1 became more correlated with local activity, and more similar to one another. In contrast, the neurons in the retrosplenial cortex that were correlated with local activity when the mice were not moving became different from one another, and more correlated with activity in distant areas. This suggests that behavioral state of an animal determines how individual neurons are coupled to activity in distant regions. The authors suggest their findings support the idea that locomotion induces a major network reorganization in which the strongly locally correlated neurons become silenced, and the distally correlated neurons become “unmasked”. These changes may gate how sensory information is processed in the retrosplenial cortex.

What's the impact?

The author’s work expands upon previous findings, which had suggested neurons are primarily coupled locally, and instead shows that many cortical neurons are correlated with activity in diverse distant regions. Their work shows that behavioral state can shift how neurons are coupled both locally and distally, and that this impact of running on different brain regions is distinct, perhaps reflecting how these different areas contribute to processing information relevant to navigation.

Clancy, K et al. Locomotion-dependent remapping of distributed cortical networks. Nature Neuroscience (2019). Access the original scientific publication here.