Background: Conversational agents (CAs) are increasingly used in mental health care to enhance access and engagement. However, their safe, ethical, and user-sensitive design remains a challenge. Despite growing attention to trauma-informed approaches in human-computer interaction, there is limited work on how the trauma-informed care (TIC) framework could be applied in the design of mental health CAs and no comprehensive synthesis to date. Objective: Guided by the Substance Abuse and Mental Health Services Administration’s TIC framework, this scoping review explored how TIC principles (safety; trustworthiness and transparency; collaboration and mutuality; empowerment, voice, and choice; peer support; and cultural, historical, and gender issues) are currently represented in the design and evaluation of mental health conversational agents (MHCAs) and identified gaps and opportunities to promote more trauma-informed design practices. Methods: Online databases, as well as a secondary survey of citation lists from an initial search, were used to identify English-language journal articles and conference proceedings from 2000 to 2024 that empirically evaluated an independent, web- or app-based, unassisted CA used for mental health and included concepts from TIC. Results: Our analysis included 38 publications (n=28, 73.7%, published in 2020 or later) covering 28 distinct MHCAs. Most studies used experimental methods (n=23, 60.6%) or user studies (n=11, 28.9%), with samples skewed toward female (men: mean 34.92%, SD 18.64%), young in age (mean 32.52, SD 14.6 y), and predominantly nonclinical (n=29, 76.3%). MHCAs were largely rule-based prototypes. No studies explicitly referenced the TIC framework as a guiding lens for MHCA design or evaluation. A total of 26 studies referenced terminology from TIC core principles but rarely defined them, while all 38 included language that could be linked to one or more principles. Overall, TIC-related concepts appeared most often within intervention design descriptions, qualitative assessments, or as items embedded in questionnaires evaluating broader constructs. Trustworthiness and transparency, safety, empowerment, voice and choice, and collaboration and mutuality were comparatively well addressed, while peer support and cultural, historical, and gender issues were largely absent. Design recommendations, where present, were relatively broad and emphasized secure, customizable, reliable, human-like, and context-sensitive MHCAs that offered multimodal interaction, goal setting and tracking, and transparency. Conclusions: Studies did not self-identify as using Substance Abuse and Mental Health Services Administration’s framework for TIC, making it more difficult to identify its elements. The fragmented terms, disciplines, and metrics used make it difficult to draw more systematic conclusions about the current research landscape related to TIC, but our analysis indicates TIC to be a descriptive and potentially unifying framework and provides a starting point for the explicit trauma-informed MHCA research and design.
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‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class
What happens when the scalability and redosability of messenger RNA (mRNA) is combined with the durability and programmability of gene therapy?
According to Serif Biomedicines, a five-year-old startup that emerged from stealth mode this month, the result is “modified DNA,” a new class of therapeutics designed to be programmable, durable, scalable, and redosable—while minimizing the drawbacks of both mRNA and gene therapy.
Modified DNA builds upon generative protein and mRNA platforms created by Flagship Pioneering, the venture capital giant which founded Serif in 2021. On April 21, Flagship formally launched Serif with an initial commitment of $50 million in financing—capital that Serif intends to use toward developing its scalable platform for optimizing and manufacturing Modified DNA treatments, aided by artificial intelligence (AI), and advancing its first drug discovery programs.
“The reason we’re bringing the company out of stealth mode now is we think we have made progress. We’ve made real progress that we’re excited to share with the world, that we’re excited to get feedback from the broader scientific community on, and we want to tell that story more broadly,” Jacob (Jake) Rubens, PhD, Serif’s co-founder and CEO, and an Origination Partner at Flagship Pioneering, told GEN.
“It’s been on our minds for a long time: What might be possible when DNA becomes an engineerable biotechnology for the first time?”
It’s a question pursued by numerous researchers and companies over the years as they sought to capitalize on DNA’s qualities of being a durably expressing molecule capable of coding for any gene, producing proteins or RNAs in a cell-specific way, as well as being scalable to manufacture and capable of re-dosing for patients.
“Those are, I think, the key differentiating attributes of theoretical DNA medicines. So the question for us became not, would this be valuable if we could do it, but why hasn’t anyone done it yet?” Rubens explained. “We’ve known about the centrality of DNA in biology, the central information molecule in DNA. We’ve known this for 75 years since Watson and Crick’s seminal discoveries around how the structure of DNA enabled it to function as an information molecule.”
Two key problems
“And when we looked at this space,” he continued, “we saw that there were two key problems: The first is that DNA is a highly inflammatory molecule. The second is that DNA needs to be delivered not just into a cell, but into the nucleus, the center of the cell.”
To create Modified DNA, Serif alters the structural and chemical form of DNA in order to minimize innate immunogenicity as lipid nanoparticles drop off the DNA not in the nucleus, but in the cytoplasm of the cell.
Once inside the cell nucleus, Modified DNA reverts to unmodified DNA, enabling transcription into therapeutic RNA and proteins. The resulting treatments are designed to last longer, be given more than once, and be programmed for cell-specific expression. To enhance durability, Serif delivers with its Modified DNA proteins which help the DNA access the nucleus. The proteins, called mRNA co-factors, are designed to transiently express proteins that enhance entry into the nucleus and gene expression.
Pending an announcement it expects to make later this year, Serif isn’t revealing specifics of its initial drug discovery programs, except to say that they focus on rare diseases and immune programming.
“This is not meant to be a limited list of where we could go but the areas that we think we’re going to go first, which are likely in addressing protein deficiencies in genetic diseases,” Rubens said.
Modified DNA has shown itself to be disease agnostic, he added, reflecting DNA’s qualities as a general, programmable information molecule: “One of the reasons we’re so excited about, the future of modified DNA as a new biotechnology akin to RNA, akin to protein, is its centrality in biology. It is the fundamental information molecule inside of all of us, inside of every living thing on this planet. So that is really the existence proof that it is generalizable.”
Tolerability and sustained expression
Also later this year, Serif plans to present data at an as-yet-unspecified scientific conference that will show modified DNA’s tolerability in non-human primates, as well as sustained gene expression with therapeutic effects in preclinical models following intravenous (IV) administration.
Serif aims to transform Modified DNA into treatments as effectively and commercially successfully as Amgen, Genentech (now a member of the Roche Group), and later Regeneron did with engineered proteins, as Alnylam Pharmaceuticals did with small interfering RNA (siRNA), and as Moderna more recently accomplished with mRNA—most notably in developing its SpikeVax® COVID-19 vaccine, which the FDA authorized for emergency use in 2020 and fully approved in 2022.
Flagship launched Moderna in 2010; the company went public in 2018 by raising $604 million, the largest-ever U.S. biotech initial public offering (IPO) until Kailera Therapeutics raised $625 million earlier this month.
At Flagship, Rubens is a scientist entrepreneur who leads the firm’s Pioneering Business Unit, which establishes and grows companies based on new biotechnology. In addition to Serif, Rubens co-founded Quotient Therapeutics, which develops therapies based on its somatic genomics platform; Tessera Therapeutics, which writes therapeutic messages into the genome through a genome engineering approach called GeneWriting
; and Sana Biotechnology, a developer of treatments based on engineered cells. He also launched Kaleido Biosciences, a microbiome therapeutics company that ceased operations in 2022.
Before joining Flagship, Jake received his PhD in microbiology from MIT, working with Tim Lu, MD, PhD, a core member of the Synthetic Biology Center, through the support of a National Science Foundation Graduate Research Fellowship. At MIT, Jake helped enable “intelligent” cell therapies by inventing gene circuits that allow engineered cells to do novel analog, digital, and hybrid computations.
Based in Cambridge, MA, Serif employs about 50 people and as of Wednesday was disclosing five open positions on its website in its three areas of focus: Chemistry (associate scientist and senior scientist, both specializing in LNP formulations), Molecular Biology (research associate and senior scientist), and Research/Discovery (scientist specializing in bioanalytical assays).
“I’m not at this point going to provide any guidance on how much more we will or won’t grow,” Rubens said. “We’re quite agile and responsive to the company’s needs.”
The post ‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class appeared first on GEN – Genetic Engineering and Biotechnology News.
Genoarchitecture and input–output organization of the mouse basal ganglia and thalamic parafascicular nucleus
Nature Neuroscience, Published online: 28 April 2026; doi:10.1038/s41593-026-02253-9
The authors investigate the transcriptomic and connectivity organization of the basal ganglia and parafascicular nucleus. The analyses suggest that combinatorial gene expression underlies the modular and cell-type-specific basal ganglia input–output networks.
Medication Treatment for Tics and Tourette’s
There are several kinds of medication than can help kids with Tourette’s or another tic disorder. But it’s important to note that not all kids who develop tics need treatment. Tics are very common. They often go away on their own, and they tend to bother parents more than they do the children experiencing them. Drawing attention to them can make them worse. So doing nothing can be the best strategy — at least initially.
Treatment comes into play if tics are upsetting your child, giving them pain, or making it hard for them to function in everyday life — say they’re disrupting class or getting bullied because of their tics.
The first recommended step in treatment is a specialized form of therapy called comprehensive behavioral intervention for tics (CBIT). CBIT is centered on habit reversal training, in which the child learns to recognize when they have an urge to tic and substitute a competing response — an easier, more comfortable, or less noticeable action or behavior that makes the tic impossible. For instance, if a child’s tic is jerking their head to the side, the strategy might be to put their chin down instead.
But if therapy isn’t effective in reducing a child’s tics, medication can help.
Guanfacine and clonidine for tics
First-line medications for Tourette’s and other tic disorders are a class of drugs called alpha-2 agonists, explains Paul Mitrani, MD, PhD, a child and adolescent psychiatrist at the Child Mind Institute. Alpha agonists decrease the release of a neurotransmitter called norepinephrine, which stimulates the nervous system. Alpha agonists serve as a kind of dimmer switch — by calming down the system, they make the urge to tic less frequent, less intense, and by extension, easier to control.
The two alpha-2 agonists usually prescribed for tics are guanfacine and clonidine. Dr. Mitrani reports that he usually starts by prescribing guanfacine because it comes in a longer-acting form (Intuniv), which reduces symptoms for a full 24 hours. Clonidine’s long-acting form (Kapvay) is effective for 12 hours.
Dr. Mitrani adds that there is a new liquid form of clonidine called Onyda XR that lasts 24 hours, but there isn’t yet a strong body of evidence regarding its effectiveness for tics. Onyda XR is FDA-approved for ADHD, as are Kapvay and Intuniv.
While no alpha agonist medications are FDA-approved specifically for tics, Kapvay and Intuniv are frequently used off-label for them. There is ample research on their effectiveness for tics, and they are recommended by clinical practice guidelines.
Some children respond better to several doses of short-acting guanfacine or clonidine, Dr. Mitrani notes, rather than a smoother dose of a long-acting medication. This may be because medication can be timed to peak at times when kids need tic suppression most, such as at school.
Alpha agonists are the preferred first line medications for tic disorders because their side-effects, including drowsiness and low blood pressure, are relatively mild.
Antipsychotics for tics
If alpha agonists aren’t helping, the next step would be to try an antipsychotic medication, which can be more effective for treating tics, Dr. Mitrani notes, but their side effects are potentially more difficult to tolerate.
Aripiprazole (Abilify), which is FDA-approved for tics, is often Dr. Mitrani’s first choice among the antipsychotic medications. Abilify is a second-generation, or atypical, antipsychotic, a group of medications that have fewer side effects than older antipsychotics. Side effects of Abilify can include restlessness, agitation and weight gain.
Haloperidol (Haldol) is also effective for tics, but it’s an older antipsychotic with more side effect concerns, Dr. Mitrani notes. “I’ve only had one patient ever on Haldol, and he tolerated it well and it really helped with his tics when other things did not.”
Risperidone (Risperdal) is another atypical antipsychotic that can help, but its side effects tend to be worse than Abilify. Risperidone can cause more concerning weight gain and metabolic, neurological, and hormonal changes that can be harmful. Sometimes other medications are used to manage the weight gain from antipsychotics.
When kids with tics also have ADHD
More than three-quarters of kids diagnosed with a tic disorder also have another disorder. When a child has multiple disorders, a clinician will want to evaluate which is causing the child the most difficulty and prioritize treating that.
The most common co-occurring disorder with tics is ADHD. “If tics are the bigger problem, we would start with treating them,” says Dr. Mitrani. “If the ADHD is the bigger problem, which it typically is, we usually treat that first.”
In the past, it was recommended that children with tics and ADHD avoid stimulant medication, based on research that showed it made tics worse. But newer studies counter that finding, Dr. Mitrani notes, concluding that the old research was based on very high doses of amphetamine-based medications. To lower the risk of exacerbating tics, he recommends starting kids with ADHD and tics on methylphenidate-based medication.
“If your child is starting a stimulant,” he adds, “and you see worsening of tics — and it’s clearly related to when the stimulant is in their system — the best approach might be a lower dose of stimulant combined with guanfacine or clonidine.”
One advantage to that combination, he notes, is that kids with ADHD who have behavior problems can benefit from the guanfacine or clonidine being active in the mornings before the stimulant starts working and in the evenings when it’s out of their system.
Kids with other co-occurring disorders
When children with tics have other co-occurring disorders, such as anxiety, OCD, or depression, treating them with medication needs to be done very carefully, Dr. Mitrani says. Since children are typically not bothered by the tics themselves, it’s almost always the other disorder that is more problematic for them. And, he adds, when the other problems cause distress, it can make the tics worse.
For anxiety, OCD, and depression, the first-line medication treatment is an antidepressant. Antidepressants can actually help alleviate tics indirectly, since they reduce anxiety. “Stress increases tics, so if there is significant anxiety and you treat the anxiety, the tics may get better,” Dr. Mitrani says. “And then maybe you don’t need the guanfacine or clonidine. But again, it depends on what the co-occurring disorders are and what’s the bigger problem for the child.”
Monitoring medication for tics
Due to the waxing and waning nature of tics, it can be challenging to see the full effect of medication and other interventions. It is important to give medication enough time to work, Dr. Mitrani notes, typically a few weeks, to see if the overall pattern, frequency, and severity of tics has improved. And children who are being treated should continue to be monitored regularly for any changes, as tics can recur or worsen, especially when a child is excited, tired, or experiencing more stress.
Most children with tics see a natural improvement or even resolution of tics as they progress through adolescence. If there seems to be a long-standing improvement, it is appropriate to consider reducing or stopping medication, especially if the child is experiencing side effects, Dr. Mitrani notes. If tics continue and are causing distress, it is important to keep treating them.
A child going off any of these medications — alpha agonists or antipsychotics — should do so gradually, by having their dose reduced over weeks or even longer, to avoid unpleasant or dangerous side effects of sudden withdrawal.
The post Medication Treatment for Tics and Tourette’s appeared first on Child Mind Institute.
GABA-Based Target for Alzheimer’s Therapy Identified
Researchers at the University of Galway have found evidence that targeting inhibitory signaling in the brain may help address cognitive dysfunction in Alzheimer’s disease (AD), a finding that runs counter to current therapeutic approaches that focus on influencing excitatory pathways. The research, published in Neuropharmacology, identifies how modulation of gamma-aminobutyric acid (GABA) signaling can restore disrupted neural balance and improve memory-related function in AD disease models.
“Given the ever-increasing burden of Alzheimer’s disease, the urgent need for the identification of novel targets for the development of disease-modifying therapy is clear,” said senior author Andrea Kwakowsky, PhD, associate professor of pharmacology and lead researcher at the School of Medicine, University of Galway.
Alzheimer’s disease is characterized by progressive cognitive impairment and is associated with hallmark pathological features including β-amyloid (Aβ) plaques and neurofibrillary tangles. In addition to these, disruption of the brain’s excitatory/inhibitory (E/I) balance has gained traction as a central mechanism contributing to memory loss. Today, most approved therapies for AD target excitatory neurotransmitter systems such as cholinergic and glutamatergic pathways, but “the symptomatic relief provided by these therapies is only marginal, and the progression or underlying causes of the disease are not addressed,” the researchers noted.
For their work, the University of Galway team instead focused on the inhibitory side of this balance, specifically the role of gamma-aminobutyric acid (GABA), the brain’s main inhibitory neurotransmitter. GABA regulates neuronal activity and is essential for maintaining stable network function and memory processes. In AD, however, E/I balance becomes dysregulated with increased extracellular GABA—triggered in part by Aβ—leading to overactivation of certain GABA receptors, particularly α5-containing GABA type A receptors (α5-GABA ARs), which are abundant in the hippocampus. The result is a dampening of neuronal signaling and which impairs learning and memory.
“Our research is significant in that it demonstrates that if we block this GABA receptor activity in nerve cells we can reverse Alzheimer-like effects caused by amyloid beta and improve cognitive performance,” Kwakowsky said.
To test whether blocking a5-GGABA A could help restore E/I balance, the team investigated α5IA, an α5-GABA AR-selective inverse agonist. α5IA works by reducing the activity of α5-GABA ARs, which decreases excess tonic inhibition. The data showed that in experimental models of AD, the compound improved long-term potentiation (LTP), a mechanism of synaptic plasticity and memory, reduced abnormal inhibitory conductance, and restored spatial memory performance.
Mechanistically, α5IA appears to act by restoring physiological levels of inhibition in the hippocampus which is critical for memory formation. By reducing excessive tonic inhibition, it rebalances E/I signaling, which allows neuronal circuits to function more effectively. “The data presented here suggest that in both ex vivo and in vivo AD models, α5IA improves cognitive function by restoring CA1 tonic inhibition, thereby re-establishing E/I balance and ameliorating the abnormal hippocampal network activity induced by Aβ1-42,” the researchers wrote.
This new study is the latest to indicate that targeting inhibitory neurotransmission could be an effective treatment approach for AD. Earlier research has shown that α5-GABA AR modulation enhances memory and reduces inhibitory signaling in both animal models and humans. But most of these studies have not directly examined the effect of α5IA in chronic neurodegenerative disease models.
The researchers noted there are some limitations to their work, pointing out that while α5IA improved cognitive outcomes, it did not reverse neuronal loss in vivo, suggesting that its effects may be primarily functional rather than neuroprotective at later stages of AD. Also, variability in drug exposure and timing may influence outcomes. Finally long-term use of α5IA has also been associated with safety concerns at high doses, including renal toxicity, so further research is needed to determine toxicity and dosing regimens and limits.
Nonetheless, the implications of this research indicate there is potential to develop new AD therapies that directly target network dysfunction rather than focusing solely on amyloid accumulation or excitatory signaling. By restoring E/I balance, this approach shows the potential to improve cognitive function even when AD pathology has taken root. The findings could also benefit diagnostic methods, as biomarkers of inhibitory dysfunction or altered GABA signaling could help identify patients who would benefit an approach that rebalances E/I signaling.
The post GABA-Based Target for Alzheimer’s Therapy Identified appeared first on Inside Precision Medicine.
Altered static and dynamic regional homogeneity in basal ganglia–thalamocortical circuits and their association with neuropsychiatric manifestations in Wilson’s disease
PurposeWilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B mutations, resulting in impaired copper metabolism and progressive neuropsychiatric manifestations. This study investigated spatiotemporal alterations in regional brain activity using static and dynamic resting-state fMRI with regional homogeneity (ReHo), and their relationships with clinical features.MethodsResting-state fMRI data were acquired from WD patients and healthy controls (HCs). Static and dynamic ReHo analyses were performed to characterize local synchronization strength and temporal variability of spontaneous neural activity. Group differences were assessed across the basal ganglia, thalamus, cerebellum, and cortical regions. Associations between altered ReHo metrics and clinical measures were evaluated with FDR correction for multiple comparisons.ResultsCompared with HCs, WD patients exhibited widespread ReHo abnormalities involving the basal ganglia (putamen and globus pallidus), thalamus, cerebellum, and cortical regions. Static ReHo in the left putamen and globus pallidus was positively associated with anxiety severity, while right putaminal ReHo was negatively associated with neurological severity and positively associated with disease duration. Dynamic ReHo in the left middle frontal gyrus showed negative associations with depression severity and disease duration. All brain–behavior correlations survived FDR correction, indicating robust effects.ConclusionWD is characterized by disrupted spatiotemporal organization of local functional synchronization within cerebellar and basal ganglia–thalamo–cortical circuits. These findings support a network-level dysfunction model involving subcortical synchronization deficits and cortical temporal instability, which together underpin neuropsychiatric manifestations and disease progression.
Twelve-month outcomes and comparative costs of internet-delivered psychodynamic therapy versus cognitive-behavioral therapy for adolescent depression: a randomized controlled trial
IntroductionAdolescent depression poses a major public health concern with substantial clinical and societal implications. Both internet-delivered cognitive behavioural therapy (ICBT) and internet-delivered psychodynamic therapy (IPDT) have shown efficacy, but questions remain regarding long-term efficacy and cost-effectiveness. The present study presents a 12-month follow-up and cost-comparison from a randomized controlled trial (RCT) comparing ICBT and IPDT for adolescent depression.MethodsParticipants were 272 adolescents aged 15–19 with a primary diagnosis of major depressive disorder. The primary outcome was depressive symptoms measured with the QIDS-A17-SR while the secondary outcome was anxiety symptoms measured with the GAD-7. Costs were assessed both by comparing costs of treatment and healthcare use 12-month post-treatment using the TIC-P.ResultsResults were stable at the 12-month follow up compared to treatment endpoint, for both depressive and anxiety symptoms. There were no significant group differences at the 12-month follow-up. There were no differences in treatment costs or in costs for healthcare use one-year post-treatment.DiscussionThis study suggests that treatment gains from IPDT and ICBT for adolescent depression remain stable during a 12-month follow-up period, with no differences between the treatments one-year post-treatment. Furthermore, it suggests comparable costs for the treatments. Interpretation of health-care use data was restricted due to the COVID-19 pandemic taking place during the follow-up period. This adds to the literature suggesting that ICBT and IPDT can be seen as viable alternatives for treating adolescent depression. More research into the long-term effects and cost-effectiveness is needed.
Tunneling Neurons in Adult Bird Brains Provide New Insights into Neurogenesis
Despite its small size—it could sit in the palm of your hand—the zebra finch is a remarkable learner. A songbird native to Australia, it’s renowned for its ability to pick up new songs. That talent has made it a favorite of scientists studying how animal brains imprint new skills, particularly vocal learning, or the capacity to perfect new sounds.
Researchers at Boston University, working with scientists at the Max Planck Institute for Biological Intelligence and the MRC Laboratory of Molecular Biology, have now discovered another quirk to the zebra finch brain—one that could also have implications for understanding our own. In a study that looked at the bird’s brain in unprecedented detail, the scientists uncovered new insights into neurogenesis—the birth, migration, and maturation of neurons—that may help the brain learn, add new skills, and restore and repair itself.
Observing the finch brain using a high-powered microscope, the researchers watched as new neurons made their way through the brain en route to bolstering existing circuits and connections. The expectation was that these neurons would step around established brain structures, including more mature brain cells, to better preserve them. Instead, the investigators saw the neurons tunnel right through. According to the BU-led team, the findings could help explain human vulnerability to a range of brain disorders. The researchers also noted that cell tunneling is used by some metastatic cancer cells.
“We found that in songbirds, new neurons in the adult brain behave like explorers forging a path through a dense jungle,” said Benjamin Scott, PhD, a BU College of Arts & Sciences assistant professor of psychological and brain sciences and the study’s corresponding author. That may help them learn new things or repair damage, but it could come with a cost to existing cells and memories—and that might be why neurogenesis is, in humans, something that doesn’t seem to extend beyond the womb. “This potentially disruptive behavior may help explain why humans and other mammals have limited capacity to regenerate brain tissue in adulthood,” commented Scott, “leaving us more vulnerable to neurodegenerative disorders such as Alzheimer’s disease.”
Scott is senior and corresponding author of the team’s published paper in Current Biology, titled “Songbird connectome reveals tunneling of migratory neurons in the adult striatum,” in which the researchers commented that their collective findings “… suggest that migrating neurons may physically reshape the mature circuit to reach their targets, revealing an unexpected degree of structural and functional plasticity in the adult brain.”
At birth our brains have pretty much all the neurons they are ever going to have. Other organs—from your skin to your heart—might get frequent cell updates, but the brain is working on version 1.0. That’s true for most mammals, but not for fish, reptiles, and birds—their brains get a regular refresh.
“This raises two questions,” said Scott, who’s also affiliated with BU’s centers for neurophotonics, photonics, and systems neuroscience. “Why do other species have high rates of neurogenesis throughout life and why is it so restricted in humans? And is there something we can learn from their biology that we might be able to harness in future?”
Scott typically studies the neural circuits that control behavior in humans and other mammals, but chose the zebra finch to investigate neurogenesis because it has a reputation as a champion species—it’s really good at generating new neurons. “Songbirds are valuable model organisms for the study of neuron migration in the adult brain,” the authors wrote. “In these species, new neurons integrate into brain regions that control complex learned behaviors, where they establish synapses with mature neurons and respond to sensory stimuli.”
However, the team pointed out, a key question is how these new neurons interact with mature circuit structures in the brain. “It is not known whether neurons pursue migratory routes that flexibly avoid these structural obstacles or deform surrounding tissue to reach their targets,” they wrote. “While prior studies have examined the molecular mechanisms and functional consequences of adult neurogenesis, few have investigated the physical interactions between migrating neurons and their surrounding microenvironment.”
For their newly reported study the team used electron microscopy (EM)-based connectomics to examine how migrating neurons interact with mature circuit elements. “We applied a new tool to study this process [neurogenesis] called electron microscopy-based connectomics—basically a really high-powered microscope—to image these cells at a very high resolution,” Scott explained. “Our first hope was just to say, what does this look like at a detail we couldn’t see before?”
Their resulting data revealed intricate interactions between migratory neurons in the adult striatum and their environment, but also showed up the tunneling neurons. “Our findings support a model in which migrating neurons disperse throughout dense neural tissue in multiple directions, making various contacts with surrounding structures,” the team wrote in summary. “In addition, our data reveal a previously undescribed form of neuron migration in which new neurons cause deformities in nearby neurons and synapses.”
The authors say that, to their knowledge, tunneling migration by neurons hasn’t previously been reported in the vertebrate nervous system. It’s possible that this is due to the constraints of study methods used, but it’s also possible that tunneling is a specialization of neurogenesis in birds.
If these new neurons are deforming brain tissue, commented Scott, are they also disrupting memories along the way? And, if neurogenesis comes with a cost, how does that balance against the brain’s capacity for learning new things and repairing after injury? And as the authors pointed out, “Interestingly, tunneling-like behavior has been described in metastatic cancer cells, which navigate confined spaces by actively deforming their microenvironments. Tunneling may therefore reflect a conserved strategy adopted by specialized migratory cell types in dense tissues.”
Scott has two—as yet untested—hypotheses for what the findings might mean for the human brain. The first is that our brains evolved to limit neurogenesis after birth as a form of protection—a way of making sure determined neurons couldn’t barge through mature connections and damage memory storage. “There is an alternative framing that is more optimistic,” he also noted. “Our discovery of tunneling shows how cells can move without glia scaffolds.”
These are the structures that operate as highways for migrating neurons. “Most glia scaffolds are lost in humans after birth, and this loss was thought to be an obstacle for neurogenesis in the adult brain,” says Scott. “However, our work shows that new neurons in the bird do not need this glia scaffold. This is exciting because it means that brain repair may not require specialized glia scaffolds.” That opens the door for scientists to explore potential stem-cell therapies that would spark neurogenesis in humans.
In summary, the authors wrote, “These results reveal the value of applying EM connectomics to adult neurogenesis and suggest that migratory neurons may dramatically perturb the existing functional circuits as they migrate and integrate. Furthermore, they reveal the remarkable structural flexibility of mature neural circuits.”
In current studies, Scott and the team in his BU Laboratory of Comparative Cognition are digging into the biology driving neurogenesis to uncover which genes are regulating the process. Much of the work merges ideas and tools from biomedical engineering and neuroethology, the study of the mechanisms underpinning animal behavior.
“Right now, we’re using a technique called single-cell RNA sequencing to identify genes that are expressed by these new neurons as they migrate,” said Scott. “We want to know what other cells they’re talking to as they move and how they are speaking to these different cells.” That’ll help them figure out whether neurons warn other cells they’re traveling through and how they know where to stop and integrate with a current circuit.
“We share a lot with our animal relatives on this planet,” noted Scott. And, while the term “bird brain” might be an insult, by learning more about the biology of songbird brains, he says, we could learn some remarkable things about our own.
The post Tunneling Neurons in Adult Bird Brains Provide New Insights into Neurogenesis appeared first on GEN – Genetic Engineering and Biotechnology News.
Aberrant local and global neural activation patterns in pediatric Prader–Willi syndrome
PurposeAlthough cognitive disorders in children with Prader–Willi syndrome (PWS) are linked to abnormalities in spontaneous neural activation and functional connectivity (FC), the specific neural activation patterns remain uncertain, especially in young children with PWS.MethodsThe current study set out to explore specific local and global neural activation in pediatric PWS using the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and seed-based whole brain FC. Information was gathered from 35 pediatric PWS patients and 33 healthy controls (HC). Both groups’ ALFF and ReHo values were computed, and FC were constructed on the basis of altered ALFF and ReHo regions. The relationships between altered ALFF, ReHo, and FC and the Griffiths Developmental Scales (GDS) of the PWS group were analyzed using partial correlation analysis.ResultsBoth ALFF and ReHo exhibited decreases in occipital lobe, temporal lobe, and cingulate gyrus, and altered ReHo was present in parietal lobe, frontal lobe, and basal ganglia areas. Moreover, ALFF and ReHo also exhibited increases in occipital and temporal lobes. Decreased FC was detected in the visual network (VN), sensorimotor network (SMN), salience network (SAN), and default mode network (DMN). The SMN-, cingulate-, and occipital lobe-related neural activation patterns were significantly positively correlated with the GDS score.ConclusionThe PWS group was characterized mainly by decreased neuronal physiological function and the ReHo was similar to ALFF but more extensive. The decreased local and global brain neural activation patterns may serve as early physiological indicators of cognitive abnormalities.
Cerebellar dysconnectivity in schizophrenia spectrum: task-based functional connectivity analysis and cognitive stratification
IntroductionSchizophrenia is conceptualized as a disorder of brain network dysconnectivity, yet relationships between neural alterations, cognitive deficits, and genetic risk remain unclear.MethodsWe examined 86 participants: schizophrenia patients (SCZ), unaffected siblings (SCZ-SIB), healthy controls (CON), and control siblings (CON-SIB). We used a multiscale graph-theoretic analysis of task-based fMRI during N-back working memory and unsupervised clinical-cognitive clustering.ResultsWe found that reduced cerebellum-sensorimotor (CER-SM) and cerebellum-cingulo-opercular (CER-CO) connectivity during the 1-back condition robustly discriminated SCZ from CON (AUC = 0.89). Critically, these dysconnectivity patterns were linked to clinical state, present in SCZ vs. SCZ-SIB but absent in SCZ-SIB vs. CON-SIB, suggesting illness expression rather than familial risk. Unsupervised clustering revealed three data-driven subtypes with distinct cognitive- symptomatic profiles: subtype 1 with relative preservation of verbal abilities (predominantly controls), subtype 2 with marked fluid cognitive impairment (enriched in SCZ), and subtype 3 with intermediate performance with working memory sparing (mixed composition). Cerebellar-cortical hypoconnectivity showed graded alignment across these profiles.DiscussionThese findings demonstrate that cerebellar dysconnectivity is most detectable under moderate cognitive load, tracks with clinical state, and covaries with transdiagnostic cognitive profiles, advancing circuit-based understanding of schizophrenia heterogeneity.