Research in Neuroscience Center focuses on molecular and cellular neuroscience, developmental neuroscience, cognitive and systems neuroscience, and basic research of the diseases of the nervous system. At the moment the Center hosts 12 research groups.
Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. The Trophin lab is investigating the role of neurotrophic factors and their receptors in neuronal plasticity and drug responses in developing and adult brain. We have particularly focused on the role of the neurotrophin BDNF (brain-derived neurotrophic factor) and its receptor TrkB in neuronal plasticity and we have shown that antidepressant drugs and anesthetic agents activate BDNF signaling through TrkB. We have further found that antidepressants reactivate developmental-like plasticity in the visual cortex and fear extinction circuitry in the adult brain in rodents. When drug-induced plasticity is combined with training or rehabilitation, maladaptive networks wired by an abnormal early life environment can be beneficially rewired in adulthood, which might explain why a combination of antidepressants with psychotherapy work better than either treatment alone. We are now focusing on the neuronal and molecular mechanisms underlying drug-induced TrkB signaling and investigating how adult plasticity could promote recovery in a variety of neuronal disorders. The lab has been supported by the European Research Council Advanced investigator award and grants from Sigrid Jusélius Foundation and Academy of Finland
Alzheimer’s disease (AD), the most common form of dementia, is quickly becoming the most expensive disease of our times. It was recently estimated that the current annual worldwide expenditure for dementia care (~450 billion €) already equals 1% of global GDP. Currently, only symptomatic treatment options are available for AD. Although recent AD research has focused on how to reverse or delay the cerebral amyloid pathology, amyloid-based therapies have not translated well into humans. Thus, Alzheimer’s disease, particularly its sporadic late-onset form, needs to be approached from various perspectives.
The functionality of all cells depends critically on protein-protein interactions (PPI), particularly on the formation of multi-protein complexes. The traditional methods for studying PPIs rely on steady-state analysis of protein complexes that have been extracted from their native cellular environment. This is a significant shortcoming for functional studies. We use Protein-fragment Complementation Assays (PCA), a novel group of methods that allows studying dynamics of PPIs in live cells, to understand basic molecular mechanisms involved in pathophysiology of neurodegenerative diseases. Currently, our focus is on normal cellular regulation of β-amyloid precursor protein (APP) and microtubule-associated protein Tau, molecules that are involved in amyloid plaque and neurofibrillary pathologies in AD, respectively. Our technology platform allows various types of approaches, including mechanistic studies and screening of novel small-molecule modulators of PPIs.
Using the PCA technology, we have recently discovered a mechanism how GABAA receptor activity regulates Tau phosphorylation. GABAA receptor is a target of many psychoactive drugs, such as benzodiazepines, and we are now working to understand what is the role of Tau in these drug responses. In another project, we have revealed a novel mechanism how neuronal apoptosis is regulated by proprotein convertase PCSK9 and lipoprotein receptors ApoER2 and VLDL receptor. These findings are connected to neuronal cholesterol metabolism, an important player in both AD pathophysiology and neuronal plasticity.
Our research has focused on the role of ion-regulatory proteins in the control of neuronal excitability at the molecular, single-cell, network and in vivo levels.
- We have identified the first human KCC2 mutation. This missense variant is a susceptibility gene for febrile seizures and perhaps other seizure disorders.
- A novel project has been started focusing on the role of the HPA axis on brain pH regulation and neuronal excitability. This work aims at elucidating the molecular mechanisms underlying birth-asphyxia seizures and brain trauma.
- The neuronal chloride extruder KCC2, a key molecule in GABAergic inhibition, upregulated following neonatal seizures, which is opposite to seizure effects in the mature brain. Our work points to age-dependent differences in the effects of neurotrophic factors on the trafficking of KCC2.
- The neuronal carbonic anhydrase isoform 7 (CA7) has turned out to be a key molecule in seizure generation and a promising anticonvulsant drug target. Using a novel CA7 KO, as well as CA2 KO and double CA7/CA2 KO mice, we have examined the roles of these isoforms in neuronal pH regulation and in the establishment of excitatory bicarbonate-dependent GABA responses during hippocampal development.
- Experimental febrile seizures (FS) cannot be evoked in the CA7 KO mice. The lack of FS is likely to be caused by a change in neuronal pH responsiveness, and not due to an absence of hyperthermia-induced hyperventilation.
- We have shown that 5% CO2 is a potent anticonvulsant in animal models and human epilepsy patients.
- We have developed a novel rodent model of birth asphyxia. Two-photon pH imaging in vivo as well as extracellular pH recordings have shown that birth asphyxia leads to a rise in both intra- and extracellular pH in the brain. The experimental birth-asphyxia seizures can be suppressed by preventing the fast rise in brain pH during recovery. A retrospective clinical study is in progress.
- Using specific ablation of the cortical subplate in neonatal rats, we have examined activity-dependent structural and functional (EEG) development of the neocortex.
Formation of neuronal circuits is a dynamic process of rapid and concurrent formation and elimination of synaptic connections. During this early development immature neuronal networks typically display spontaneous, rhythmic activity, which is thought to be instrumental in development of the circuitry. How exactly activity shapes synaptic connectivity during development and the molecular mechanisms underlying these processes are not fully understood. The key questions focus on the cellular and molecular mechanisms that link electrical activity to changes in the structure and function of immature synapses and how these are regulated during development. To shed light on these mechanisms, we focus on the development of glutamatergic circuitry in the limbic system, and in particular, on the role of ionotropic glutamate receptors in this process. We aim to understand how the fast Hebbian and the slow, homeostatic plasticity mechanisms operate in the developing circuitry and how they control the transition from immature to mature type synaptic and circuit function. In addition, we are interested to understand how genetic and /or external disturbance influences developmental fine-tuning of the limbic networks and how aberrant development may affect behavior and vulnerability to neuropsychiatric disorders later on in life. Our experimental approach involves the use of in vitro electrophysiological techniques in combination with pharmacological and local genetic manipulation in various neuronal preparations.
Increasing number of mouse models is used in the basic biomedical and preclinical research. At the same time, serious concerns have been expressed regarding the validity and reproducibility of animal studies. Therefore, clear demand exists for further research on mouse behavioural biology in laboratory conditions for improving the translational potential. The central problems are the role of environment and animal itself (sex, genetic background). Environmental interventions can be the most powerful methods for enhancing the disease modelling in animals. On the other hand, better methods and consideration of species-specific and ethological paradigms are the key issues in animal-based research. Finally, reporting of animal studies requires improvement and transparency regarding the above mentioned aspects.
The focus of my research is at studying the effects of different housing and testing conditions, husbandry and experimenters on mouse behaviour. Therefore, we are applying a range of behavioural tests to male and female mice of different inbred strains after combination of various environmental treatments or manipulations (caging – open or individually ventilated, nesting materials, other enrichment items, social and individual housing, handling methods, experimenters etc.).
In contrast to classical behavioural testing, where animals are moved to the novel arenas for a brief moment, novel home cage technologies capture the animal behavior 24/7. It is easy to argue, that these methods will become increasingly more important in comprehensive analysis of disease models, allowing sensitive detection of circadian patterns, progression of disease symptoms or outcome of treatment attempts. In my project, automated behavioural monitoring and testing of socially housed mice (IntelliCage) is applied for better understanding and characterization of social behaviour and cognitive performance. IntelliCage can be viewed as a standard environment where the mice are left undisturbed by experimenter and variety of pre-programmed experiments can be applied. We want to expand the application of IntelliCage by developing and validating additional and new protocols for evaluation of behavioural responses related to social interaction, stress, addiction.
Experiments are carried out at the Mouse Behavioural Phenotyping Facility, in close collaboration with other local research groups using behavioural methods, allowing implementation and testing of findings and protocols in different genetically modified mouse lines.
The overall aim of the project is refinement of the methods used for behavioural assessment of mouse models and simultaneously enhance knowledge related to laboratory animal welfare.
Spontaneous brain activity fluctuates in time scales spanning at least across five orders of magnitude. These fluctuations have also been observed on all studied spatial (anatomical) scales and they are statistically governed by spatio-temporal power-laws. Such a scale-free organization at a macroscopic level, however, contrasted by salient scale-specificity of neuronal activities, i.e. neuronal oscillations, in the moment-by-moment brain dynamics. We aim to elucidate how scale-free and scale-specific brain dynamics together are correlated with and causally related to variability in human sensory perception, cognitive performance, and motor output. To this end, we have developed methods for quantification of neuronal scaling-laws as well as for mapping dynamic neuronal interaction networks from invasive and non-invasive electrophysiological recordings of human brain activity. We are also developing an integrated neuroinformatics platform for project and data management, analysis, visualization, data sharing, and joint methods/model development. Spatio-temporal and –spectral interaction maps comprise samples of task-dependent human dynamic connectome. We expect an accumulation of this connectome map to yield decisive insight into the mechanisms that coordinate neuronal activity both into transient scale-specific neuronal ensembles and into overall scale-free dynamics. These mechanisms may be critical for coherent perceptual, cognitive, and motor operations as well as in the emergence of scale-free fluctuations in human behavioral performance, respectively.
Our lab investigates the functional relevance of neuronal dynamics and large-scale neuronal interactions in human cognition.
In humans, attention, working memory, and consciousness are fundamental cognitive functions, which are serial, introspectively coherent, and have a limited capacity of a few objects. Furthermore, the behavioral performance in any sustained behavioral task fluctuates in a scale-free manner and is clustered into sequences of similar behaviors. These phenomena and psychophysical task performance are highly variable across individual subjects.
Our lab aims to reveal the systems-level neuronal mechanisms underlying these functions and the variability in behavioral performance. We record neuronal activity with an excellent temporal resolution from healthy human subjects by using magneto- and electroencephalography (M/EEG) and from epileptic patients with intracranial EEG (iEEG). We then use transcranial magnetic stimulation (TMS) to test the causal role of these neuronal activities and interactions in coordinating behavioral performance.
A central topic in our research is to elucidate the functional roles of synchronization and multi-band oscillations in these cognitive functions and the putative role of cross-frequency interactions as a mechanism for the integration of spectrally and temporally distributed processing. We also investigate their functional significance in neuropsychiatric diseases and as well as the changes that cortical oscillations and synchronization undergo during developmental and experience-dependent plasticity.
As a second research line, we address the role of neuronal criticality in shaping the neuronal activity in long time-scales and in sustained behavioral tasks.
The modulatory neurotransmitters activate G protein-coupled receptors, which share signal transduction systems in cells. In addition to regulating key physiological functions, these systems are involved in human mental and neurological diseases. We are particularly interested in the histaminergic system, which interacts with other systems such as the dopaminergic, GABAergic and glutamatergic ones in regulation of, for instance, sleep, diurnal rhythms, feeding, and addiction.
In a mouse model, lack of histamine in the brain of histidine decarboxylase-deficient mice was associated with an altered ethanol-induced locomotor response. H3 receptor antagonists inhibited the ethanol-evoked conditioned place preference whereas an agonist did not. Acute stimulatory response by ethanol was also modulated by H3 receptor ligands. An antagonist increased ethanol activation, whereas agonist pretreatment diminished it. The inhibition of ethanol reward by H3 receptor antagonism implies that H3 receptor is a potential target to suppress compulsory ethanol seeking. In a postmortem human study, H3 receptor radioligand binding was higher in the prefrontal cortex of schizophrenic brains than in control subjects, suggesting that histamine through this receptor may regulate cortical functions important in psychiatric diseases.
Zebrafish has become a useful tool to study the interactions of the modulatory neurotransmitter systems. The two tyrosine hydroxylases (th1 and th2) in zebrafish brain showed complementary expression patterns. Translation inhibition of the PARK6 gene (PINK1) important in early-onset Parkinson’s disease led to decreased neuron numbers in dopaminergic cell groups expressing either th1 or th2. A decline in neuron numbers was associated with decreased locomotor activity of the fish, suggesting that these neurons are functionally important. Inhibition of PINK1 translation also rendered the fish sensitive to subeffective doses of MPTP, indicating interactions of genetic and environmental factors relevant in Parkinson’s disease. Using microarray analyses, several novel signaling pathways related to PINK1 knockdown were identified and verified functionally. Histaminergic neurons are found around the largest th2 neuron group in zebrafish brain. Knocking down histidine decarboxylase abolished the dark induced flash response of larval fish, and decreased the number of hypocretin neurons. The effect was mimicked by histamine H1 receptor antagonists, suggesting that histamine through this receptor controls the hypocretin system.
Our group focuses on mechanisms of neuronal development and plasticity. Based on neurite outgrowth assays, we have previously isolated, cloned, and produced as recombinant proteins two ligands of heparan sulfate proteoglycans (HSPGs), HMGB1 (high-mobility group B1; amphoterin) and HB-GAM (heparin-binding growth-associated molecule; pleiotrophin).
In addition to heparin/heparan sulfates, HMGB1 binds to the immunoglobulin superfamily protein RAGE (receptor for advanced glycation end-products), which mediates the neurite outgrowth-promoting signal of HMGB1. In addition to growth cone migration, HMGB1/RAGE regulates migration and proliferation of many cell types during development, tumor spread, and inflammation. Studies using the zebrafish model have recently identified HMGB1 as an essential gene for forebrain development.
AMIGO (amphoterin-induced gene and orf) has been identified as an HMGB1-induced gene in hippocampal neurons using ordered differential display. AMIGO defines a novel gene family with three closely related members (AMIGO, AMIGO 2, and AMIGO 3) that belong to both LRR (leucine-rich repeat) and Ig (immunoglobulin) superfamilies of cell surface proteins. We have recently identified AMIGO as an auxiliary subunit of the Kv2.1 potassium channel. Furthermore, AMIGO affects the channel activity and thereby excitability of neurons.
HB-GAM regulates migration of neurons in developing brain through binding to the transmembrane proteoglycan syndecan-3 (N-syndecan). Furthermore, syndecan-3 acts as a cell surface receptor for GDNF (glial cell-derived neurotrophic factor)-family neurotrophic factors. In addition to HSPG binding, HB-GAM has similar carbohydrate binding sites in chondroitin sulfate proteoglycans (CSPGs). CSPGs are major inhibitory regulators of plasticity and regeneration in the CNS extracellular matrix but our recent experiments have shown that their role can be reversed from inhibition to activation by HB-GAM in the extracellular space. We are currently developing novel treatment strategies for CNS injuries based on the ability of HB-GAM and similar glycosaminoglycan-binding molecules to induce regenerative growth of neurites.
Chloride homeostasis is an important mechanism involved in a variety of cellular events such as volume regulation, proliferation and migration. In neurons the setting of intracellular chloride concentration is in addition crucial for the changes GABAA mediated transmission that take place during development and trauma. These changes are regulated by the functional expression of the chloride transporters KCC2 and NKCC1. Our group has been particularly interested in the interplay between neurotrophic factors and chloride homeostasis. Because neurotrophic factors are regulated by neuronal activity and can regulate inhibitory synapses, they are key molecules to mediate developmental and adult forms of synaptic plasticity during physiological and pathophysiological conditions. In this regard our group has been successful as we have elucidated part of the mechanisms involved in the interplay between intracellular chloride regulation and neurotrophic factors in developing neurons as well as in clinically important paradigms for epilepsy and CNS injury. Neurodegeneration is a devastating sequel common to many neuropathological conditions. A current view is that the brain reacts to pathological insults by activating developmental like programs for survival, regeneration and replacement of damaged neurons. For instance, after injury mature central neurons become dependent on BDNF trophic support for survival. The reasons for this dependency are poorly studied. In resent works we descried a novel mechanism explaining the neuroprotective action of BDNF after trauma: a) we found that the post-traumatic effect of GABAA receptors is set by the down-regulation of the K-Cl cotransporter KCC2 and functional presence of Na-K-Cl cotransporter NKCC1; b) post-traumatic GABA depolarization induces p75NTR up-regulation that promotes death signalling; c) BDNF trophic support counterbalance this death signalling and thus exerts a neuroprotective action. However the intrinsic mechanism causing trauma induced decrease of KCC2, BDNF requirement for neuronal survival and consequent rearrangement of post-traumatic network are not known. We are currently testing how global this mechanism is in different in vivo trauma models. Our current strategy is to develop tools to investigate in more detail this mechanism with the aim to find novel and refined therapeutically approaches to tackle neurodegeneration.
The major function of K-Cl cotranporter KCC2 is to extrude chloride. Resent results have shown that the developmental up-regulation of KCC2 is important for the formation of dendritic spines and formation of glutamatergic synapses. Intriguingly this is not mediated by its chloride extrusion activity but through the interaction of KCC2 with intracellular proteins. We have now found a number of new intracellular proteins that mediates the regulatory action of KCC2 on the actin cytoskeleton. Our future aim is the implement these tools to investigate the structural role of KCC2 in dendritic spine plasticity and the interplay between inhibitory and excitatory transmission during development and trauma.
Our final aim is to define the role of the interplay between the proteins regulating chloride homeostasis and neurotrophic factors in neuronal wiring and rewiring in the developing and post-traumatic brain.
Interactions between genetic and epigenetic factors guide the brain to form from initially randomly connected set of nerve cells to a delicate neuronal network. Concomitantly, intrinsic and sensory input-driven patterns of synchronous electrical activity form ‘functional templates’, which are then converted into stable yet modifiable synapses. These processes define the opening and closing of critical period windows in the brain. Thus, much of the capabilities and limitations of the brain’s later functions and plasticity are set during these periods. Accordingly, these developmental processes can also predispose the brain to various diseases manifested only later in life. Glutamatergic synapses are highly modifiable structures representing the basic units of information processing in the mammalian brain. In addition to rapidly transmitting excitatory signals from neuron to neuron, these synapses have a remarkable capability for activity-dependent plasticity, a process underlying neuronal development as well as adult learning and memory. To this end, we have identified a kainate-type glutamate receptor (KAR) that regulates presynaptic maturation in developing hippocampal neurons (Lauri et al. 2006). It provides a novel mechanism for activation of ‘silent’ synapses during early development and is thus likely to play a critical role in the formation of functional synaptic connections in the hippocampus. In general, we aim to understand how neuronal activity shapes glutamatergic synaptic connectivity during development and what are the mechanisms underlying these processes. We are particularly interested in how the hippocampal synaptic network is fine-tuned by homeostatic and Hebbian mechanisms during the development, and how are these processes associated with the emergent network properties (e.g. synchronous oscillations) in the brain’s limbic areas. We use wide range of in vitro and in vivo electrophysiological approaches in combination with molecular biological techniques to explore the functional development of the brain.
Mitochondrial dysfunction has shown out to be a common cause of human inherited disease, with amazing clinical variability, from neonatal fatal multisystem disorders to diabetes, neurodegeneration, dysfertility or tumorigenesis of adult age. Mitochondrial disorders show a wide variation in individual disease severity and progression. Up to date, only few therapy options are available to a limited number of patients.
Our research group focuses in clarifying the molecular basis of mitochondrial disorders, with a special emphasis on neurodegeneration. We search for disease genes in human sample materials, characterize disease phenotypes and set up DNA-based diagnosis, create disease models based on identified gene defects and utilize these models to study molecular pathogenesis and to test potential treatments.
The specific focus of our group is the disorders involving mitochondrial DNA (mtDNA) maintenance. A plethora of nuclear-encoded proteins are involved in replication, repair and transcription of mtDNA, as well as its copy number regulation. In particular, we clarify the functions of DNA polymerase gamma, the replicative mtDNA polymerase, and its functional companion Twinkle, the replicative helicase. We and others have shown that both of these proteins are involved in a wide variety of dominantly and recessively inherited neurodegenerative disorders, such as MIRAS (mitochondrial recessive ataxia syndrome), Parkinsonism and childhood/juvenile onset epilepsies.
The ultimate aim of our research group is to generate enough knowledge on the mitochondrial disease mechanisms to be able to create therapy. Due to the variability of mitochondrial disease phenotypes, however, it is unlikely that a single therapy would be beneficial for all kinds of mitochondrial dysfunction.
Our group works in close contact with clinical patient care, through excellent collaboration links to child neurology, neurology and pathology departments of Helsinki University and to hospitals throughout Finland, as well as through our responsibilities in HUSLab mitochondrial disease diagnosis.
See website for Academy of Finland Centre of Excellence FinMIT - Research on Mitochondria, Metabolism and Disease