Swedish Research Council grants awarded to researchers at the Department of Neuroscience
Eight researchers at the Department of Neuroscience have been awarded project grants from the Swedish Research Council in the category of medicine and health.
Gilad Silberberg, is awarded SEK 9 000 000 during a five-year period for the project Brain circuits for sensorimotor decision-making in health and disease.
How brain circuits are organized to support decision-making is a fundamental question in neuroscience. Decision-making involves two principal processes, the integration of sensory information and execution of the goal-directed behavior. This project aims to unravel neural mechanisms for sensorimotor decision-making in health and disease.
A central brain region controlling sensorimotor functions is the striatum, the input structure of the basal ganglia. One role of the striatum is the selection of specific actions out of a vast repertoire of possible behaviors broadcasted from cortex. Such action selection is a function of concerted activity of different cell types, shaped by different neuromodulatory systems. Aberrant neuronal activity and neuromodulation in striatal circuits are the cause of disorders such as Parkinson’s disease, ADHD, OCD, and more, affecting both motor and sensory functions. Previous studies of striatal function have focused on the role of individual neuromodulators, often studied separately.
"Little is known about the interactions between different neuromodulators and their dynamics across the two striatal hemispheres. Recent studies in the Silberberg lab have shown reciprocal interactions between dopaminergic and cholinergic systems, and bilateral sensorimotor signals in the striatum. We aim to build on these findings and unravel the key neural and neuromodulatory mechanisms in the striatum supporting sensorimotor decision-making in healthy and Parkinsonian mice", says Gilad Silberberg.
Jan Mulder is awarded SEK 7 200 000 during a four-year period for the project Detailed molecular dissection of the human brain in health and disease.
The brain is the most complex organ of the human body involved in many vital body functions. The large repertoire of diverse function requires specialized proteins expressed by specialized cells and cellular networks that drive physiology. This project builds on previous work on mapping protein expression and distribution in the human brain and brain of other mammalian species which is summarized in an open access brain section in the human protein atlas. It aims to further increase our understanding of the cellular and molecular organization of the brain by increasing completeness (more regions, more species), resolution (single cell) and depth of analysis (rare proteins).
Recent development in spatial transcriptomics enables genome wide detection of transcripts with a subcellular resolution. It is now possible to map protein expression of single cells with known spatial location. These methods will be used to investigate the ‘healthy’ and neurodegenerative disease affected human brain with a focus on molecular signatures of individual cells, local cell-cell interactions and disease associated changes in gene expression.
Another knowledge-gap is the understanding of species differences and human brain specific molecular features. This information is crucial for understanding human disease, modeling human disease, and treating human disease.
"The goal of the mammalian RNA atlas is to provide a holistic view on protein expression in all major tissues of human, pig, macaque, mouse, rat and dog. All together these research efforts and created resources aim to facilitate basic research and development of better diagnoses and treatments of human diseases", says Jan Mulder.
Daniela Calvigioni is awarded SEK 6 000 000 during a four-year period for the project Sexual dimorphism in anxiety disorders: multi-node time map of maladaptive developing brain circuits.
Anxiety is a major global health issue, is highly prevalent (30 percent among adults worldwide) and is characterized by significant life impairment. Women have two times increased risk of developing anxiety compared to men, with an increased sensitivity starting from an early age (for example 38 percent of adolescent girls in Sweden self-reported stress and anxiety feelings).
To develop effective treatment strategies, which are currently lacking for a large portion of patients, it is essential to define the physiology, pathophysiology and critical windows of key brain circuits that shape the manifestation of anxiety disorders.
"My approach, long-term vision and methodology strive to ultimately uncover how single neurons encode stimuli of emotional valence in the healthy brain in vivo and identify how activity modes and genetic cell states ultimately drive the behavioral transition to anxiety disorders", says Daniela Calvigioni.
Researchers are trying to understand why women are more likely to develop anxiety, and why adolescence is a critical period for this. It may be that certain changes in the brain occur during this time, or that certain environmental factors have a greater impact during these years.
"By understanding the neurobiology behind the processing of emotional stimuli within specific brain circuits and their maladaptive transition to a pathological state, we hope to ultimately develop more effective treatments for anxiety", Daniela Calvigioni adds.
Juan Pablo Lopez
Juan Pablo Lopez is awarded SEK 6 000 000 during a four-year period for the project Psychedelic compounds: mechanisms, circuits and behavioral outcomes of antidepressant treatment response.
According to the world health organization, more than 150 million Europeans live with a mental health condition, and only a small fraction of them receive the care they need. Notably, these disorders are more prevalent in women and are associated with an economic burden of 100 billion SEK/year in Sweden alone.
"Our project aims to understand the behavioral language, molecular mechanisms, and cellular circuits responsible for the rapid-acting effects of novel antidepressant treatments, using both male and female mice. We offer a comprehensive, ethologically-minded, and holistic approach to mouse phenotyping, combined with state-of-the-art molecular and viral-mediated gene manipulations", says Pablo Lopez.
The series of studies proposed in this project are innovative and have the potential to change our understanding of stress-related psychiatric disorders and their treatments.
Tibor Harkany is awarded SEK 4 800 000 during a four-year period for the project Neuron-glia interactions in the hypothalamus, and their sensitivity to psychoactive drug abuse.
The abuse of illicit substances and prescription drugs is a growing problem in society. These drugs can have harmful effects on the brain and body, including impacts on cognition, food intake, stress sensitivity and reproduction. The hypothalamus, the neuroendocrine center of the brain, plays an important role in controlling these functions. Disorders of the hypothalamus can lead to neuropsychiatric consequences. The brain consists not only of neurons, but also of glial cells, including astroglia, which could be affected by illicit drugs, but how and to what extent is still unknown.
Research suggests that astroglia in the hypothalamus may play an important role in how drugs affect the brain, as they express the receptors and transporters that illicit drugs bind to. Changes in astroglia can affect neuronal activity and lead to various diseases.
"Here we will investigate how two commonly used drugs, amphetamine and cannabinoids, by using glial cells as 'gateways' to the brain, can affect hypothalamic circuits and endocrine functions. 'By using a combination of experimental neurobiology, molecular genetics, neuropsychopharmacology and single cell analysis, we hope to understand more about how these drugs affect the brain", says Tibor Harkany.
The researchers are also exploring the possibility of using genetic tools to restore the properties of astroglia that may have been damaged by drug exposure. This could potentially lead to new therapeutic strategies to treat the harmful effects of drug use.
Janos Fuzik is awarded SEK 2 400 000 during a three-year period for the project All-optical Dissection of Hypothalamic and Periaqueductal Inhibitory Circuits of Female Panic Disorder.
Human and animal studies come together to shed light on the role of the ventromedial hypothalamus (VMH) in panic disorder (PD). The VHM is the part of the brain that plays a central role in regulating many of the body's basic functions such as satiety, for example.
A technique called alloptical voltage imaging has been used to examine how neurons communicate with each other in large groups within the periaqueductal (PAG) and anterior hypothalamic (AHN), two important parts of the brain that play roles in different functions. Among other behaviors, PAG controls freezing while AHN drives escape thus VMH controls both in the fight or flight system. The maladaptation of these pathways can contribute to anxiety disorders.
"This helps us understand how these communication pathways can be disrupted in PD. We combine this technique with something called Voltage-Seq, which gives us a detailed picture of which genes are active in PAG and AHN neurons. By comparing these gene expression profiles, we can gain a better understanding of how these neurons function and how they may be affected in PD", says Janos Fuzik.
Specific communication pathways are also examined between VMH and PAG, and VMH and AHN, in both female and male mice, to see if there are any sex-specific differences that can explain why women are more often affected by PD.
"In this way, we hope to contribute to a better understanding of PD and perhaps even find new treatment methods in the future", Janos Fuzik adds.
Emanuela Santini is awarded SEK 2 400 000 during a three-year period for the project Altered dopamine neurotransmission and repetitive behavior in autism spectrum disorder.
Autism Spectrum Disorder (ASD) encompasses a range of lifelong disorders characterized by shared behavioral traits, including repetitive behaviors and social deficits. The impact of repetitive behaviors on individuals with ASD is significant, yet there is a noticeable lack of effective pharmaceutical interventions for this aspect of the disorder. Additionally, the study of repetitive behaviors lags behind other aspects of ASD, emphasizing the need to unravel the neural changes that underlie these behaviors and to develop novel treatments.
Various genetic models of ASD, such as Fragile X syndrome (FXS) and the eIF4E mice—developed in our research—have shed light on the contribution of disrupted neuronal signaling processes, particularly protein synthesis, to the emergence of ASD-like behaviors, including repetitive behaviors. Findings from both clinical studies involving ASD patients and investigations utilizing preclinical models consistently highlight the malfunction of the striatum, a brain region responsible for regulating motor and cognitive functions, as a pivotal factor in the development of repetitive behaviors. The proper functioning of the striatum is contingent upon the physiological activity of dopamine, a neurotransmitter associated with pleasure and reward.
"Our research aims to elucidate whether impaired dopamine neuromodulation in the striatum contribute to repetitive-like behaviors in animal models of ASD, utilizing the eIF4E model. Given the low prevalence of the eIF4E genetic variant in ASD, we will also leverage the FXS model, representing the most common genetic form of ASD. This dual approach seeks to uncover whether altered dopamine levels represent a shared neurological anomaly across various forms of ASD", says Emanuela Santini.
Agneta Richter-Dahlfors is awarded SEK 2 400 000 during a three-year period for the project Biofilm in urinary tract infections.