Researchers Link Brain Memory Signals to Blood Sugar Levels

A set of brain signals known to help memories form may also influence blood sugar levels, finds a new study in rats.

Researchers at NYU Grossman School of Medicine discovered that a peculiar signaling pattern in the brain region called the hippocampus, linked by past studies to memory formation, also influences metabolism, the process by which dietary nutrients are converted into blood sugar (glucose) and supplied to cells as an energy source.

The study revolves around brain cells called neurons that “fire” (generate electrical pulses) to pass on messages. Researchers in recent years discovered that populations of hippocampal neurons fire within milliseconds of each other in cycles. The firing pattern is called a “sharp wave ripple” for the shape it takes when captured graphically by EEG, a technology that records brain activity with electrodes.

Published online in Nature, the new study found that clusters of hippocampal sharp wave ripples were reliably followed within minutes by decreases in blood sugar levels in the bodies of rats. While the details need to be confirmed, the findings suggest that the ripples may regulate the timing of the release of hormones, possibly including insulin, by the pancreas and liver, as well of other hormones by the pituitary gland.

“Our study is the first to show how clusters of brain cell firing in the hippocampus may directly regulate metabolism,” says senior study author György Buzsáki, MD, PhD, the Biggs Professor of Neuroscience in the Department of Neuroscience and Physiology at NYU Langone Health.

“We are not saying that the hippocampus is the only player in this process, but that the brain may have a say in it through sharp wave ripples,” says Dr. Buzsáki, also a faculty member in the Neuroscience Institute at NYU Langone.

Known to keep blood sugar at normal levels, insulin is released by pancreatic cells, not continually, but periodically in bursts. As sharp wave ripples mostly occur during non-rapid eye movement (NREM) sleep, the impact of sleep disturbance on sharp wave ripples may provide a mechanistic link between poor sleep and high blood sugar levels seen in type 2 diabetes, say the study authors.

Previous work by Dr. Buzsáki’s team had suggested that the sharp wave ripples are involved in permanently storing each day’s memories the same night during NREM sleep, and his 2019 study found that rats learned faster to navigate a maze when ripples were experimentally prolonged.

“Evidence suggests that the brain evolved, for reasons of efficiency, to use the same signals to achieve two very different functions in terms of memory and hormonal regulation,” says corresponding study author David Tingley, PhD, a postdoctoral scholar in Dr. Buzsáki’s lab.

Dual Role

The hippocampus is a good candidate brain region for multiple roles, say the researchers, because of its wiring to other brain regions, and because hippocampal neurons have many surface proteins (receptors) sensitive to hormone levels, so they can adjust their activity as part of feedback loops. The new findings suggest that hippocampal ripples reduce blood glucose levels as part of such a loop.

“Animals could have first developed a system to control hormone release in rhythmic cycles, but then applied the same mechanism to memory when they later developed a more complex brain,” adds Dr. Tingley.

The study data also suggest that hippocampal sharp wave ripple signals are conveyed to hypothalamus, which is known to innervate and influence the pancreas and liver, but through an intermediate brain structure called the lateral septum. Researchers found that ripples may influence the lateral septum just by amplitude (the degree to which hippocampal neurons fire at once), not by the order in which the ripples are combined, which may encode memories as their signals reach the cortex.

In line with this theory, short-duration ripples that occurred in clusters of more than 30 per minute, as seen during NREM sleep, induced a decrease in peripheral glucose levels several times larger than isolated ripples. Importantly, silencing the lateral septum eliminated the impact of hippocampal sharp wave ripples on peripheral glucose.

To confirm that hippocampal firing patterns caused the glucose level decrease, the team used a technology called optogenetics to artificially induce ripples by re-engineering hippocampal cells to include light-sensitive channels. Shining light on such cells through glass fibers induces ripples independent of the rat’s behavior or brain state (e.g., resting or waking). Similar to their natural counterparts, the synthetic ripples reduced sugar levels.

Moving forward, the research team will seek to extend its theory that several hormones could be affected by nightly sharp wave ripples, including through work in human patients. Future research may also reveal devices or therapies that can adjust ripples to lower blood sugar and improve memory, says Dr. Buzsáki.

Amygdala Found to Have Role in Important Pre-Attentive Mechanism in the Brain

We’re all familiar with the startle reflex – that sudden, uncontrollable jerk that occurs when we’re surprised by a noise or other unexpected stimulus. But the brain also has an important pre-attentive mechanism to tamp down that response and tune out irrelevant sounds so you can mind the task in front of you.

This pre-attentive mechanism is called sensorimotor gating and normally prevents cognitive overload. However, sensorimotor gating is commonly impaired in people with schizophrenia and other neurological and psychiatric conditions, including post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD).

“Reduced sensorimotor gating is a hallmark of schizophrenia, and this is often associated with attention impairments and can predict other cognitive deficits,” explains neuroscientist Karine Fénelon, assistant professor of biology at the University of Massachusetts Amherst. “While the reversal of sensorimotor gating deficits in rodents is a gold standard for antipsychotic drug screening, the neuronal pathways and cellular mechanisms involved are still not completely understood, even under normal conditions.”

(Image caption: Mouse brain stem inhibitory neurons (green) activated by amygdala inputs (magenta neuronal processes))

To assess sensorimotor gating, neuroscientists measure prepulse inhibition (PPI) of the acoustic startle reflex. PPI occurs when a weak stimulus is presented before a startle stimulus, which inhibits the startle response.

For the first time, Fénelon and her UMass Amherst team – then-Ph.D. student Jose Cano (now a postdoctoral researcher at the University of Rochester Medical Center) and Ph.D. student Wanyun Huang – have shown how the amygdala, a brain region typically associated with fear, contributes to PPI by activating small inhibitory neurons in the mouse brain stem. This discovery, published in the journal BMC Biology, advances understanding of the systems underlying PPI and efforts to ultimately develop medical therapies for schizophrenia and other disorders by reversing pre-attentive deficits.

“Until recently, prepulse inhibition was thought to depend on midbrain neurons that release the transmitter acetylcholine,” Fénelon explains. “That was because studies of schizophrenia patients involved deficits in the cholinergic system.”

But there exists a “super cool neuroscience tool” – optogenetics – which allows scientists to use light to pinpoint and control genetically modified neurons in various experimental systems. “It is very specific,” Fénelon says. “Before this, we couldn’t pick and choose which neurons to manipulate.”

Their challenge was to use optogenetics to identify which circuits in which parts of the brain were involved in PPI. “We wanted to know what brain region connects to the core of the startle inhibition circuit in the brain stem, so we put tracers or dye to visualize those neurons,” Fénelon says. “With this approach we were able to identify amygdala neurons connected to the brain stem area in the center of the startle inhibition circuit.”

Next, they tested with optogenetic tools whether this connection between the amygdala and the brain stem was important for startle inhibition. “We know that in the brain of schizophrenia patients the function of the amygdala is also altered, so it made sense to us that this brain region was relevant to disease,” Fénelon says.

By photo-manipulating amygdala neurons in mice, they showed that the amygdala appeared to contribute to PPI by activating brain stem inhibitory, or glycinergic, neurons. Specifically, PPI was reduced by either shutting down the excitatory synapses between the amygdala and the brain stem or by silencing the brain stem inhibitory neurons themselves. “Interestingly, the PPI reduction measured as a result of these photo manipulations mimicked the PPI reduction observed in humans with schizophrenia and in mouse models of schizophrenia,” Fénelon says.

To better detail this connection, Fénelon and team used electrophysiology along with optogenetics to record the electrical activity of individual neurons taken from thin brain sections, in vitro. “This very precise yet technically challenging recording method allowed us to confirm without any doubt that amygdala excitatory inputs activate those glycinergic neurons in the brain stem,” Fénelon says.

She calls this finding “a piece of the puzzle” that pinpoints the prepulse inhibition circuit. Now she’s working in her lab using this new information to identify other brain pathways and attempt to reverse pre-attentive deficits in a mouse model of schizophrenia. Such a breakthrough would allow researchers to begin to develop drugs that can more precisely target treatment of pre-attentive problems.

Research Shows Promising Results for Parkinson’s Disease Treatment

Researchers from Carnegie Mellon University have found a way to make deep brain stimulation (DBS) more precise, resulting in therapeutic effects that outlast what is currently available. The work, led by Aryn Gittis and colleagues in CMU’s Gittis Lab and published in Science, will significantly advance the study of Parkinson’s disease. 

DBS allows researchers and doctors to use thin electrodes implanted in the brain to send electrical signals to the part of the brain that controls movement. It is a proven way to help control unwanted movement in the body, but patients must receive continuous electrical stimulation to get relief from their symptoms. If the stimulator is turned off, the symptoms return immediately.

Gittis, an associate professor of biological sciences in the Mellon College of Science and faculty in the Neuroscience Institute, said that the new research could change that.

“By finding a way to intervene that has long-lasting effects, our hope is to greatly reduce stimulation time, therefore minimizing side effects and prolonging battery life of implants.”

Gittis set the foundation for this therapeutic approach in 2017, when her lab identified specific classes of neurons within the brain’s motor circuitry that could be targeted to provide long-lasting relief of motor symptoms in Parkinson’s models. In that work, the lab used optogenetics, a technique that uses light to control genetically modified neurons. Optogenetics, however, cannot currently be used on humans.

Since then, she has been trying to find a strategy that is more readily translated to patients suffering from Parkinson’s disease. Her team found success in mice with a new DBS protocol that uses short bursts of electrical stimulation.

“This is a big advance over other existing treatments,” Gittis said. “In other DBS protocols, as soon as you turn the stimulation off, the symptoms come back. This seems to provide longer lasting benefits — at least four times longer than conventional DBS.”

In the new protocol, the researchers target specific neuronal subpopulations in the globus pallidus, an area of the brain in the basal ganglia, with short bursts of electrical stimulation. Gittis said that researchers have been trying for years to find ways to deliver stimulation in such a cell-type specific manner.

“That concept is not new. We used a ‘bottom up’ approach to drive cell type specificity. We studied the biology of these cells and identified the inputs that drive them. We found a sweet spot that allowed us to utilize the underlying biology,” she said. 

Teresa Spix, the first author of the paper, said that while there are many strong theories, scientists do not yet fully understand why DBS works.

“We’re sort of playing with the black box. We don’t yet understand every single piece of what’s going on in there, but our short burst approach seems to provide greater symptom relief. The change in pattern lets us differentially affect the cell types,” she said.

Spix, who defended her Ph.D. in July, is excited about the direct connection this research has to clinical studies.

“A lot of times those of us that work in basic science research labs don’t necessarily have a lot of contact with actual patients. This research started with very basic circuitry questions but led to something that could help patients in the near future,” Spix said.

Next, neurosurgeons at Pittsburgh’s Allegheny Health Network (AHN) will use Gittis’ research in a safety and tolerability study in humans. Nestor Tomycz, a neurological surgeon at AHN, said that researchers will soon begin a randomized, double blind crossover study of patients with idiopathic Parkinson’s disease. The patients will be followed for 12 months to assess improvements in their Parkinson’s disease motor symptoms and frequency of adverse events.

“Aryn Gittis continues to do spectacular research which is elucidating our understanding of basal ganglia pathology in movement disorders. We are excited that her research on burst stimulation shows a potential to improve upon DBS which is already a well-established and effective therapy for Parkinson’s disease,” Tomycz said.

Donald Whiting, the chief medical officer at AHN and one of the nation’s foremost experts in the use of DBS, said the new protocol could open doors for experimental treatments.

“Aryn is helping us highlight in the animal model things that are going to change the future of what we do for our patients. She’s actually helping evolve the care treatment of Parkinson’s patients for decades to come with her research,” Whiting said.

Tomycz agreed. “This work is really going to help design the future technology that we’re using in the brain and will help us to get better outcomes for these patients.”