Tag: Neurons

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Basolateral amygdala may play a larger, overarching role during naturalistic events

Study provides insights into how early life events can affect brain wiring patterns

The basolateral amygdala (BLA) is a region of the brain that has been almost exclusively studied in the context of fear and emotion. Only recently have researchers begun to question whether the BLA may play a larger, overarching role in memory and behavior. Yet almost nothing is known about the neuronal activity of the BLA during naturalistic behavior.

To address these questions, neuroscientists at the Sainsbury Wellcome Centre at UCL observed the neuronal activity in this brain region while rats freely engaged with a variety of different ethological stimuli. Interactions with ethological stimuli are relevant to the animal’s survival and to the propagation of its genes, and include food, prey and conspecifics. In a new study, published today in Cell Reports, the researchers demonstrate strong responses to these classes of events in the BLA.

The naturalistic stimuli in this study were important to the animals in their everyday life and the rats were naturally curious to interact with them. They included complex multisensory stimuli like male and female rats, food and a moving toy mouse.

Traditionally, research has focused on studying the BLA in rats during trained tasks. Instead, we wanted to observe neuronal activity while rats were freely behaving to see if we could find an overarching role for the BLA during natural behavior that might tie together the previous lines of research.” 

Cristina Mazuski, Research Fellow in the O’Keefe Lab, Sainsbury Wellcome Centre and lead author on the paper

Using Neuropixels, Mazuski and O’Keefe simultaneously recorded from hundreds of neurons in the rat BLA and correlated single-cell neural activity with complex behavior to identify different classes of cells within the BLA that respond to the ethological stimuli. They identified and described two novel categories of cells in the BLA; event-specific neurons, which responded to only one of the four classes of stimuli, and panresponsive neurons, which responded equally well to most or all of the stimuli.

Strikingly, 1/3 of the cells showed an active memory response: not only did the neural response last throughout the entire event but it continued after the end of the event for many minutes. The authors speculate that these after-responses might be acting as a memory system telling the rest of the brain that an important event had just occurred and perhaps alerting other brain regions to store information about other aspects of the event and the circumstances surrounding it.

Commenting on these aspects of the results, Prof. O’Keefe, the senior author on the paper, said “These findings position the basolateral amygdala at the center of the social/ethological brain and open up a whole research program investigating what other naturally-occurring stimuli the rest of the (normally silent) BLA cells are interested in. They also direct our attention to the memory functions of the amygdala which have not, to date, received sufficient consideration”.

As the researchers were recording from many neurons simultaneously using Neuropixels probes, they were also able to look at the circuit connectivity. By delving into the correlated activity between different single neurons, they could infer the flow of information from more-specific neurons such as those responding to female rats or food to the less-specific panresponsive neurons.

“This initial study opens up a lot of future avenues for research. The next steps are to find out what the responses are sensitive to, how robust they are and confirm whether they play a role in memory,” concluded Cristina.

This research received funding from the European Union’s Horizon 2020 research and innovation program under the Marie-Sklodowska-Curie grant agreement No. 840562 to Cristina Mazuski, the Sainsbury Wellcome Centre Core Grant from the Gatsby Charitable Foundation and Wellcome Trust (090843/F/09/Z), and Wellcome Trust Principal Research Fellowship (Wt203020/z/16/z) to John O’Keefe.

Source:

Sainsbury Wellcome Centre

Journal reference:

Mazuski, C & O’Keefe, J., (2022) Representation of Ethological Events by Basolateral Amygdala Neurons. Cell Reports. doi.org/10.1016/j.celrep.2022.110921.

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Study provides insights into how early life events can affect brain wiring patterns

Study provides insights into how early life events can affect brain wiring patterns

Mar 10 2022

A new study of brain development in mice shortly after birth may provide insights into how early life events can affect wiring patterns in the brain that manifest as disease later in life – specifically such disorders as schizophrenia, epilepsy and autism.

Researchers focused on two types of brain cells that have been linked to adult neurological disorders: neurons in a modulating system nestled deep in the brain and other neurons in the cortex, the brain’s outermost layer, that counteract excitation in other cells using inhibitory effects. The modulating cells send long-range cables to the cortex to remotely influence cortical cell activity.

The study is the first to show that these two types of cells communicate very early in brain development. A chemical released from the modulating cells initiates the branching, or arborization, of axons, the long, slender extensions of nerve cell bodies that transmit messages, on the cortical cells – and that arborization dictates how effective the cells in the cortex are at doing their job.

Though there is still a lot to learn about the impact of this cellular interaction in the postnatal brain, the researchers said the study opens the door to a better understanding of how neurological diseases in adults may relate to early-life events.

It’s known that abnormal early-life experiences can impact kids’ future sensation and behavior. This finding may help explain that kind of mechanism.”


Hiroki Taniguchi, associate professor of pathology, The Ohio State University College of Medicine and senior author of the study

“This study provides new insight into brain development and brain pathology. It’s possible that during development, depending on animals’ experiences, this modulating system activity can be changed and, accordingly, the cortical circuit wiring can be changed.”

Taniguchi completed the work with co-authors André Steinecke and McLean Bolton while he was an investigator at the Max Planck Florida Institute for Neuroscience.

The research is published today (March 9, 2022) in the journal Science Advances.

The study involved chandelier cells, a type of inhibitory neurons in the cortical section of the brain, and neurons of the cholinergic system – one of the systems that monitor the environment and the internal state, and send signals to the rest of the brain to trigger memory and appropriate behaviors.

“Both of these types of cells have been separately studied in the context of adult functions or modulations so far. The developmental role of cholinergic neurons in the brain wiring remains poorly understood,” Taniguchi said.

Chandelier cells are named for the spray of signal-transmitting synapses (called synaptic cartridges) at the branch terminals that resemble candles of a traditional chandelier, a pattern that gives them inhibitory control over hundreds of cells at a time.

“These cells have output control,” said Steinecke, first author of the study who is now working at Neuway Pharma in Germany. “Chandelier cells can put a brake on excitatory cells and tell them they’re not ready to fire. As inhibitory cells, chandelier cells are thought to regulate waves of firing – which is important, because the waves contain information that is transmitted over large distances of the brain.”

Previous post-mortem studies have shown that the synaptic terminals located at the end of chandelier cell axons appear to be reduced in the brains of patients with schizophrenia.

“This axonal ‘arbor’ being reduced suggests they don’t make as many connections to downstream targets, and the connections themselves are also altered and don’t work that well,” Steinecke said.

The team used two techniques to observe chandelier cells during early-life brain development in mice: genetically targeting and using a dye to label and detect cells that differentiate into chandelier cells, and transplanting genetically manipulated cells back into animals shortly after birth. “This enabled us to watch brain development as it happens and manipulate conditions to test what the mechanisms are,” Taniguchi said.

The researchers first observed how chandelier cell axons develop their branching structures, noting that small protrusions emerging from axons were the first signs that branches would sprout. And they identified the chemical needed to start that sprouting process – the neurotransmitter acetylcholine, which is released by cholinergic system cells.

The interaction between the distant cell types was confirmed through a series of experiments: Knocking out receptors that bind to acetylcholine and decreasing activity of cholinergic neurons lessened branch development, and making cholinergic neurons more likely to fire led to more widespread branching.

“The key is that we didn’t previously know how neuromodulatory systems regulate the cortical circuits – and both of them have been implicated in brain diseases,” Taniguchi said. “Now that we’ve found that cholinergic neurons could remotely impact cortical circuit development, especially cortical inhibitory signals, the question is what kind of environment or emotional state of change can impact cortical inhibitors’ development? We may want to see if we can find a link as a next step.”

This work was supported by funding from the Max Planck Society and the Brain Behavior and Research Foundation.

Source:

Journal reference:

Steinecke, A., et al. (2022) Neuromodulatory control of inhibitory network arborization in the developing postnatal neocortex. Science Advances. doi.org/10.1126/sciadv.abe7192.

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Cell stress-related biochemical events may be partly driving Parkinson’s disease

Cell stress-related biochemical events may be partly driving Parkinson's disease

Parkinson’s disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study from scientists at Scripps Research.

The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.

We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain.”


Stuart Lipton, MD, PhD, study senior author, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research

Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.

In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.

One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including “housekeeping” systems that normally keep protein aggregates under control.

In the new study, the Scripps Research team demonstrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson’s, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

“The process we observed seems very similar to what is seen in Parkinson’s and LBD brains,” says study first author Chang-Ki Oh, PhD, a staff scientist in the Lipton laboratory.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas-;supporting the idea that this process occurs in humans.

Lipton and Oh say that S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to develop such compounds as potential commercial drugs, they could, in principle, slow the Parkinson’s/LBD disease process or prevent its further spread in the brain after it begins, Lipton says.

Source:

Scripps Research Institute

Journal reference:

Oh, C., et al. (2022) S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson’s Disease and Lewy Body Dementia. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.1508-21.2022.