“Start cells” in the midbrain control whether we walk or run
A study by researchers at Karolinska Institutet and the University of Copenhagen published in Nature provides new and important knowledge about how the brain controls locomotion. In research on mice, scientists have discovered that specific start cells in various locations in the brainstem control whether the mouse walks or runs. This research may lead to new treatments for diseases and injuries that adversely affect locomotion.
Locomotion, or the ability to move from one place to another is a fundamental and necessary function for the survival of both people and animals. Locomotor behaviour is episodic in character, meaning that we move as and when we want or need to, and that we are able to easily interrupt ongoing movements. At the same time, locomotion is executed at different speeds to regulate how fast we travel from one place to another depending on the context or purpose that drives us e.g. slowly exploring the neighborhood in a new city or fast escaping an oncoming threat.
The precise coordination of locomotion is controlled by neural circuits in the spinal cord, but it is the brainstem that sends signals to the spinal cord to initiate, stop and modulate these movements. Still, how is the start and speed control executed? By which command pathways? And can these command pathways be recruited to support different types of locomotion dependent on the behavioural context?
Part of a larger neural network
In the present study, the researchers Vittorio Caggiano, Roberto Leiras, Haizea Goñi-Erro, Debora Masini, and colleagues together with Professor Ole Kiehn who led the study, address these questions. They have identified specific “start cells” that are important for initiation, speed and context dependent selection of locomotion in mice. These ‘start cells’ are part of a larger neural network located in two different areas of the midbrain, the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF).
“By identifying the midbrain ‘start neurons’ we complement a previous study in which we discovered specific ‘stop cells’ in the brainstem that perform the opposite task of making the mouse stop. Together, these cell types appear to be crucial to the episodic control of locomotive behaviour,” explains Professor Ole Kiehn, who works both at Karolinska Institutet’s Department of Neuroscience and at the Department of Neuroscience at the University of Copenhagen.
Used light and designer drugs
The researchers have utilised a number of advanced techniques, including optogenetics, to study which types of neurons are involved and the location of the neural networks. By using light and designer drugs, they have been able to activate or inactivate selected groups of nerve cells and then study how this affects the locomotor output in mice.
They found that, in contrast to what has previously been thought, excitatory projection neurons in both PPN and CnF can start locomotion and contribute to the maintenance and speed regulation of slower locomotion. However, only CnF is able to elicit high-speed escape locomotor activity. In contrast, activity in PPN neurons favours explorative locomotion.
“We have demonstrated that both brain regions collaborate and work independently of one another to select the gait and speed of locomotion,” says Ole Kiehn.
Could be similar mechanisms in humans
The researchers believe that similar mechanisms are at work in the selection of locomotion and speed in humans. The results of the study can therefore be important in developing treatments for spinal cord injuries and certain diseases that adversely affect locomotion. Parkinson’s Disease, where gait disturbances and freezing of gait are very pronounced, affects an area of the brain that sends signals to the PPN. By implanting fine electrodes in the brain – a technique called deep brain stimulation which is already used to treat some symptoms in Parkinson’s disease – circuits in either CnF or PPN might now be targeted with new precision and used to increase the locomotor capabilities. Similar approaches may also be used after damage to the spinal cord, where initiation of locomotion is strongly affected.
The research was funded by the European Research Council (LocomotorIntegration), the US National Institute of Neurological Disorders and Stroke, The Swedish Research Council, StratNeuro and the Novo Nordisk Foundation- Laureate Award.
“Midbrain circuits that set locomotor speed and gait selection”
Caggiano V, Leiras R, Goñi-Erro H, Masini D, Bellardita C, Bouvier J, Caldeira V, Fisone G & Kiehn O
Nature, online 17 January 2018, doi: 10.1038/nature25448
"Kesi ya ""Start cells"" katika ubongo wa kati huamua kama mtu anatembea au kukimbia, utafiti uliofanywa na watafiti wa Karolinska Institutet na Chuo Kikuu cha Copenhagen, na kuchapishwa katika jarida la Nature, unatoa maarifa mapya na muhimu kuhusu jinsi ubongo unavyoongoza mwendo." Katika utafiti uliofanywa kwenye panya, wanasayansi wamegundua kwamba chembe za msingi katika sehemu mbalimbali za uti wa ubongo huamua kama panya anatembea au anakimbia. Utafiti huo waweza kusababisha matibabu mapya ya magonjwa na majeraha yanayoathiri vibaya mwendo wa mwili. Uhamisho, au uwezo wa kuhamia kutoka mahali moja hadi pengine, ni kazi ya msingi na muhimu kwa uhai wa watu na wanyama. Mwenendo wa locomotor ni episodic katika tabia, maana kwamba sisi hoja kama na wakati tunataka au haja ya, na kwamba sisi ni uwezo wa kwa urahisi kuvuruga harakati zinazoendelea. Wakati huo huo, mwendo unafanywa kwa kasi tofauti ili kudhibiti jinsi tunavyosafiri haraka kutoka mahali moja hadi nyingine kulingana na muktadha au kusudi linalotuendesha. Kuangalia kwa polepole eneo la mji mpya au kukimbia haraka tishio linalokuja. Utaratibu wa kusonga unadhibitiwa na mzunguko wa neva katika uti wa mgongo, lakini ni shina la ubongo linalotuma ishara kwa uti wa mgongo kuanzisha, kuacha na kurekebisha harakati hizi. Hata hivyo, jinsi gani mwendo wa kuanza na mwendo wa kasi unaendeshwa? Kwa njia zipi za amri? Na njia hizi za amri zinaweza kuajiriwa kusaidia aina tofauti za mwendo kulingana na muktadha wa tabia? Katika utafiti huu, watafiti Vittorio Caggiano, Roberto Leiras, Haizéa Goñi-Erro, Deborah Masini, na wenzake pamoja na Profesa Ole Kiehn, ambaye aliongoza utafiti, kushughulikia maswali haya. Wamegundua "chembe za kuanza" maalum ambazo ni muhimu kwa kuanzishwa, kasi na uteuzi wa hali ya kutegemea mwendo katika panya. "Seli za kuanza" ni sehemu ya mtandao mkubwa wa neva ulio katika maeneo mawili tofauti ya ubongo wa kati, kiini cha pedunculopontine (PPN) na kiini cha cuneiform (CNF). "Kwa kutambua'starten neurons' ya ubongo wa kati tunakamilisha utafiti wa awali ambao tuligundua'seli za kuacha' maalum katika shina la ubongo ambazo hufanya kazi kinyume cha kufanya panya aachane. Pamoja, aina hizi za seli zinaonekana kuwa muhimu kwa udhibiti wa vipindi vya tabia ya locomotive, "anaeleza Profesa Ole Kiehn, ambaye anafanya kazi wote katika Idara ya Neuroscience ya Karolinska Institutet na katika Idara ya Neuroscience katika Chuo Kikuu cha Copenhagen. Kwa mfano, utafiti wa utafiti wa neurogenesis unaonyesha kwamba kuna aina kadhaa za neurons zinazohusika na eneo la mitandao ya neva. Kwa kutumia dawa za kuvutia na za kubuni, wameweza kuamsha au kuzima makundi yaliyochaguliwa ya seli za neva na kisha kuchunguza jinsi hii inavyoathiri pato la locomotor katika panya. Kwa upande mwingine, neuroni za projection ya excitatory katika PPN na CNF zinaweza kuanzisha mwendo na kuchangia uhifadhi na udhibiti wa kasi ya mwendo wa polepole. Hata hivyo, tu CnF ni uwezo wa kuchochea kasi ya juu kutoroka shughuli locomotor. Kinyume chake, utendaji katika neuroni za PPN hupendelea mwendo wa kuchunguza. "Tumeonyesha kwamba maeneo yote mawili ya ubongo yanashirikiana na kufanya kazi kwa kujitegemea ili kuchagua mwendo na kasi ya mwendo", anasema Ole Kiehn. Watafiti wanaamini kwamba kuna utaratibu sawa unaofanya kazi katika uteuzi wa mwendo na kasi kwa wanadamu. Matokeo ya utafiti huo yanaweza kuwa muhimu katika kuendeleza matibabu kwa ajili ya majeraha ya uti wa mgongo na magonjwa fulani ambayo huathiri vibaya locomotion. Ugonjwa wa Parkinson, ambapo matatizo ya kutembea na kuzima kwa kutembea ni dhahiri sana, huathiri eneo la ubongo ambalo hutuma ishara kwa PNP. Kwa kupandikiza electrodes nzuri katika ubongo, mbinu inayoitwa Deep Brain Stimulation ambayo tayari hutumiwa kutibu dalili fulani katika ugonjwa wa Parkinson, mzunguko katika CNF au PNF sasa unaweza kulengwa kwa usahihi mpya na kutumika kuongeza uwezo wa locomotor. Mbinu kama hizo zaweza pia kutumiwa baada ya kuharibiwa kwa uti wa mgongo, ambapo kuanzishwa kwa mwendo huathiriwa sana. Utafiti huo ulifadhiliwa na Baraza la Utafiti la Ulaya (LocomotorIntegration), Taasisi ya Kitaifa ya US ya Matatizo ya Neurolojia na Stroke, Baraza la Utafiti la Sweden, StratNeuro na Tuzo ya Tuzo ya Novo Nordisk Foundation. "Michoro ya ubongo wa kati ambayo huweka kasi ya locomotor na uteuzi wa mwendo: Caggiano V, Leiras R, Goñi-Erro H, Masini D, Bellardi C, Bouvier J, Caldeira V, Fison G na Kiehn O Nature, online 17 Januari 2018"