Fractals in the Nervous System: conceptual Implications for Theoretical Neuroscience

This essay is presented with two principal objectives in mind: first, to document the prevalence of fractals at all levels of the nervous system, giving credence to the notion of their functional relevance; and second, to draw attention to the as yet still unresolved issues of the detailed relationships among power law scaling, self-similarity, and self-organized criticality. As regards criticality, I will document that it has become a pivotal reference point in Neurodynamics. Furthermore, I will emphasize the not yet fully appreciated significance of allometric control processes. For dynamic fractals, I will assemble reasons for attributing to them the capacity to adapt task execution to contextual changes across a range of scales. The final Section consists of general reflections on the implications of the reviewed data, and identifies what appear to be issues of fundamental importance for future research in the rapidly evolving topic of this review

Mechanotransduction and the crayfish stretch receptor

Abstract Mechanotransduction or mechanosensitivity is found in almost every cell in all organisms from bacteria to vertebrates. Mechanosensitivity covers a wide spectrum of functions from osmosensing, cell attachment, classical sensory mechanisms like tactile senses in the skin, detection of sound in hair cells of the hearing apparatus, proprioceptive functions like recording of muscle length and tension in the muscle spindle and tendon organ, respectively, and pressure detection in the circulation etc. Since most development regarding the molecular aspects of the mechanosensitive channel has been made in nonsensory systems it is important to focus on mechanosensitivity of sensory organs where the functional importance is undisputed. The stretch receptor organ of the crustaceans is a suitable preparation for such studies. The receptor organ is experimentally accessible to mechanical manipulation and electrophysiological recordings from the sensory neuron using intracellular microelectrode or patch clamp techniques. It is also relatively easy to inject substances into the neuron, which also makes the neuron accessible to measurements with fluorescent techniques. The aim of the present paper is to give an up to date summary of observations made on the transducer properties of the crayfish stretch receptor (Astacus astacus and Pacifastacus leniusculus) including some recent unpublished findings. Finally some aspects on future line of research will be presented

Mechanotransduction and the crayfish stretch receptor

Abstract Mechanotransduction or mechanosensitivity is found in almost every cell in all organisms from bacteria to vertebrates. Mechanosensitivity covers a wide spectrum of functions from osmosensing, cell attachment, classical sensory mechanisms like tactile senses in the skin, detection of sound in hair cells of the hearing apparatus, proprioceptive functions like recording of muscle length and tension in the muscle spindle and tendon organ, respectively, and pressure detection in the circulation etc. Since most development regarding the molecular aspects of the mechanosensitive channel has been made in nonsensory systems it is important to focus on mechanosensitivity of sensory organs where the functional importance is undisputed. The stretch receptor organ of the crustaceans is a suitable preparation for such studies. The receptor organ is experimentally accessible to mechanical manipulation and electrophysiological recordings from the sensory neuron using intracellular microelectrode or patch clamp techniques. It is also relatively easy to inject substances into the neuron, which also makes the neuron accessible to measurements with fluorescent techniques. The aim of the present paper is to give an up to date summary of observations made on the transducer properties of the crayfish stretch receptor (Astacus astacus and Pacifastacus leniusculus) including some recent unpublished findings. Finally some aspects on future line of research will be presented

Micromechanics of mechanoreceptors in arthropods

Die vorliegende Dissertation umfasst sechs Manuskripte und Publikationen, die sich mit den grundlegenden mechanischen Ereignissen bei der Reizung, mit den cuticularen Strukturen, deren Materialeigenschaften, und im Speziellen mit der Umwandlung der mechanischen Reize auf dem Weg zu den Dendriten der Sinneszellen (Reiztransformation) unterschiedlicher Mechanorezeptoren der Spinne Cupiennius salei befassen. Die behandelten Rezeptortypen sind einerseits Haarsensillen, die durch die Bewegung ihres Haarschafts gereizt werden, und andererseits Spaltsensillen, die auf ihre Kompression infolge von Spannungen im Exoskelett reagieren. Ein Schwerpunkt der Untersuchungen bei beiden Rezeptortypen ist der Vergleich von Propriorezeptoren, die für Bewegungen des Spinnenbeins bei der Lokomotion sensibel sind, und deren biologischer Einsatzbereich durch die Biomechanik des Beins begrenzt ist, mit exterorezeptiven Sensillen, die ein breites Spektrum unterschiedlicher Reizamplituden aus der Umwelt detektieren. Das erste Manuskript widmet sich direkt dem Vergleich eines propriorezeptiven Spaltsinnesorgans, das durch laterale Auslenkungen eines Beinglieds gereizt wird, mit einem exterorezeptiven Vibrationsrezeptor. Der Einsatzbereich des propriorezeptiven Organs wird durch die lineare Umwandlung der Reizkraft in die reizwirksame Spaltkompression gut abgedeckt. Beim Vibrationsrezeptor verläuft die Kraftumwandlung exponentiell, was zur Detektion unterschiedlicher und weitgehend unbekannter Vibrationsamplituden sinnvoll ist. Ein weiteres Manuskript behandelt die Materialeigenschaften einer viskoelastischen cuticularen Struktur, die diesem Vibrationsrezeptor auf dem Weg der Vibrationen vom Substrat vorgeschaltet ist, und die sich als effizienter mechanischer Filter für die biologisch relevanten Vibrationsfrequenzen erweist. Ein Manuskript befasst sich mit propriorezeptiven Haarsensillen, die für die Geschwindigkeit des Abbiegens eines Beingelenks sensibel sind. Bei diesem Sensillentypus sind die Eigenschaften der Haaraufhängung an die mechanischen Belastungen durch die Haarauslenkung infolge von Berührungen bei jedem Schritt der Spinne angepasst. Im Gegensatz dazu ermöglicht die Haaraufhängung der hochempfindlichen Luftbewegungsdetektoren, der Trichobothrien, die reizwirksame Bewegung des Haares durch die winzigen Kräfte, die durch Reibung mit den Partikeln der Luft entstehen (Manuskript 4). Die mechanischen Eigenschaften der Haaraufhängung der Trichobothrien stellen eine Anpassung an den oszillierenden Charakter der biologisch relevanten Luftbewegungen dar. Die Ergebnisse zeigen, dass bei den unterschiedlichen Mechanorezeptoren durch scheinbar geringe Unterschiede der mechanischen Strukturen und des beteiligten Materials (Cuticula) eine hochgradige Anpassung an den jeweiligen biologischen Aufgabenbereich erreicht wird. Diese Feinabstimmung an die relevanten Reize zeigt sich auch deutlich an den sensorischen Antworteigenschaften bei adäquater Reizung.This dissertation comprises six manuscripts and publications dealing with the basal mechanical events leading to the stimulation of different mechanoreceptors of the spider Cupiennius salei. The main focus is the transformation of the mechanical stimuli on their way to the dendrites of the sensory cells, the cuticular structures involved, and their specific material properties. The different types of mechanoreceptors are hair sensilla on the one hand, which are stimulated by the movement of their hair shaft, and slit sensilla on the other hand, which are stimulated by their compression as a consequence of strains in the exoskeleton. In both structural receptor types proprioreceptors sensible for movements of leg segments during locomotion are compared with receptors for environmental stimuli like vibrations and air flow. Whereas for the proprioreceptors the biological range of operation is limited by the biomechanics of the spider’s leg, in the exteroreceptors the stimulus amplitudes span a range of several powers of magnitude. One manuscript directly compares a proprioreceptive slit organ stimulated by lateral excursions of a leg segment with a highly sensitive exteroreceptive vibration slit sensor. The range of operation of the proprioreceptor is well covered by the linear transformation of the stimulus force to the sensory effective slit compression. In case of the vibration receptor the force transformation follows the stimulus amplitude exponentially, which is reasonable for the detection of different and widely unknown vibration amplitudes. Another manuscript deals with the material properties of a viscoelastic cuticular structure located on the way of the vibrations to the vibration receptor. By its viscoelastic material properties this cuticular structure represents an efficient mechanical filter for the biologically relevant vibration frequencies. A further manuscript addresses proprioreceptive hair sensilla sensitive for the velocity of flexion of a leg joint. Here the properties of the hair suspension are especially adapted to deal with the mechanical loads of hair deflection at every step of the spider walking. In contrast, the hair suspension of the highly sensitive air flow receptive hairs, the trichobothria, facilitates the sensory effective hair deflection by the minute forces of friction with the particles of moving air (manuscript 4). The mechanical properties of the hair suspension of the trichobothria are adapted to the oscillating nature of hair deflection due to the biologically relevant air movements. The results show that apparently small changes of the mechanically relevant cuticular structures and their material properties result in the adaption of the different mechanoreceptor types to their particular range of operation. This fine-tuning to the properties of the biological stimuli becomes even more obvious when the sensory responses to adequate stimulation are taken into account

Review of the applications of principles of insect hearing to microscale acoustic engineering challenges

When looking for novel, simple, and energy-efficient solutions to engineering problems, nature has proved to be an incredibly valuable source of inspiration. The development of acoustic sensors has been a prolific field for bioinspired solutions. With a diverse array of evolutionary approaches to the problem of hearing at small scales (some widely different to the traditional concept of "ear"), insects in particular have served as a starting point for several designs. From locusts to moths, through crickets and mosquitoes among many others, the mechanisms found in nature to deal with small-scale acoustic detection and the engineering solutions they have inspired are reviewed. The present article is comprised of three main sections corresponding to the principal problems faced by insects, namely frequency discrimination, which is addressed by tonotopy, whether performed by a specific organ or directly on the tympana; directionality, with solutions including diverse adaptations to tympanal structure; and detection of weak signals, through what is known as active hearing. The three aforementioned problems concern tiny animals as much as human-manufactured microphones and have therefore been widely investigated. Even though bioinspired systems may not always provide perfect performance, they are sure to give us solutions with clever use of resources and minimal post-processing, being serious contenders for the best alternative depending on the requisites of the problem

Mechanisms of thermal sensitivity in rodent primary afferent neurons innervating the skin

The role of temperature sensations elicited from the skin, include object identification, thermoregulation and the conscious perception of pain. Humans can differentiate at least three distinct cold sensations: innocuous cooling, cold pain and pain evoked by freezing. However, patients with painful neuropathies often suffer from cold allodynia, where normally non-painful cool stimuli begin to induce pain or cold hyperalgesia, a heightened sensitivity to a painful cold stimulus. It is therefore vital to understand the mechanisms by which cold is signalled under normal conditions and to investigate which changes occur under pathological conditions. The thesis will describe sets of electrophysiological recordings carried out from rodent primary afferent neurons using the in vitro skin nerve preparation in an attempt to reveal mechanisms underlying thermal sensitivity. The discovery of thermally sensitive transient receptor potential (TRP) ion channels has given insights into the molecular mechanisms of thermal transduction. These include the heat sensitive TRPV1 ion channel and cold sensitive TRPM8 and TRPA1 ion channels. However, the role of the TRPA1 receptor in cold transduction remains controversial. Cold sensitivity of primary afferents in adult rat was studied. Selective TRP channel agonists capsaicin, menthol, and mustard oil were then applied onto the receptive field of primary afferents to determine the expression pattern of thermosensitive TRP channels. The majority of cold sensitive A and C fibre nociceptors as well as thermoreceptors were sensitive to menthol, indicating that TRPM8 is the transducer of cold on these afferents. The poor correlation of TRPA1 expression and cold sensitivity in nociceptive A and C fibres indicates that TRPA1 is unlikely to play a significant role is detecting noxious cold. TRPV2 is another heat activated ion channel. The sensory phenotype of TRPV2 knock-out mice was studied and compared against TRPV2 wild-type mice in both hairy and glabrous skin. Mice lacking TRPV2 had normal heat sensitive nociceptors and afferents retained mechanical sensitivity. The involvement of potassium (K+) channels in mediating and/or modulating thermosensation has been suggested. Based on these previous findings, the effects of the broad spectrum potassium channel blockers 4-aminopyridine (4- AP) and Tetraethylammonium (TEA) were studied on primary afferents neurons. Application of 4-AP or TEA directly on the receptive fields induced a novel cold sensitivity in a proportion of low threshold mechanoreceptors and increased the cold responses in a proportion of cold sensitive A and C fibre nociceptors. Interestingly 4-AP or TEA had no effect on the cold responses of innocuous cold thermoreceptors. Drug induced cold sensitivity was investigated using the chemotherapeutic agent oxaliplatin, which induces a sensory neuropathy in patients. Following infusion of the drug, patients experience abnormal skin sensations (paresthesias), which are triggered or aggravated by exposures to cold. The receptive properties of afferents were investigated before and after oxaliplatin application to provide an insight into the mechanism by which this abnormal cold sensitivity develops. This study shows for the first time, that oxaliplatin applied directly on the receptive fields induces a novel cold sensitivity in half of previously cold insensitive Aβ mechanoreceptors. Just over a third of Aδ nociceptors also displayed a novel or increased sensitivity to cold after oxaliplatin application. In contrast, receptive properties of C fibres remained unchanged. Overall, the results of the thesis provide evidence that TRPM8 is involved in the transduction of cold stimuli and that potassium and sodium conductances are involved in modulating the final response to a cold stimulus.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Molecular mechanisms of nociception and pain

My thesis uses in vivo calcium imaging to investigate the cell and molecular mechanisms of two unusual pain states: congenital analgesia and cold allodynia. Genetic deletion of voltage-gated sodium channel NaV1.7 in mice and humans leads to profound pain insensitivity. Paradoxically, peripherally-targeted pharmacological antagonists of NaV1.7 fail to relieve pain in the clinic. To determine the mechanism of analgesia in NaV1.7 null mutants, I used optical, electrophysiological and behavioural methods to investigate the effect of peripheral NaV1.7 deletion on nociceptor function. Surprisingly, both calcium imaging and extracellular recording of NaV1.7-deficient sensory neurons in vivo found limited deficits in the response to noxious stimuli. Synaptic transmission from nociceptor central terminals in the spinal cord was however compromised following NaV1.7 deletion. Importantly, both synaptic deficits and behavioural analgesia were reversed by blocking central opioid receptors. Collectively, these data account for the failure of peripherally-targeted NaV1.7 blockers and point to a central mechanism of analgesia in NaV1.7 null mutants that requires opioid receptors. Chronic pain patients suffering from cold allodynia experience normally innocuous cooling as excruciating pain, but the cells and molecules driving cold allodynia remain elusive. I used in vivo calcium imaging to investigate how the activity of cold-sensing neurons was altered in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, peripheral nerve injury and ciguatera poisoning. In neuropathic mice exhibiting cold allodynia, a subset of cold-insensitive, large-diameter, peptidergic nociceptors became responsive to cooling. Diptheria toxin-mediated ablation of these silent cold-sensing neurons decreased neuropathic cold hypersensitivity. Voltage-gated potassium channels KV1.1 and KV1.2 were highly expressed in silent cold-sensing neurons and pharmacological inhibition of these channels rapidly induced cold responsiveness in cold-insensitive neurons. Taken together, I reveal that silent-cold sensing neurons contribute to cold allodynia in neuropathic pain and identify KV1 channel downregulation as a driver of de novo cold sensitivity, in vivo

Kõrgete välistemperatuuride sensoorne kodeerimine putukate antennaalsete termo- ja hügroneuronite triaadi poolt

A Thesis submitted for the degree of Doctor of Philosophy in AgricultureDespite that environmental thermal conditions play a major role in all levels of biological organization very little information is available on noxious high temperature sensation crucial in behavioural thermoregulation and survival of small ectothermic animals such as insects. Scarcely anything is known about encoding of noxious high temperatures by peripheral thermoreceptor neurons. In this thesis, using a novel focused ion beam scanning electron microscopy combined technique, it was demonstrated that in economically important carabid and elaterid beetles, thermo- and hygroreceptor neurons are located in antennal dome-shape sensilla (DSS) morphologically distinct from all known types of sensilla of other insects. They are innervated by the classical sensory triad of a cold neuron and two antagonistically responding hygroreceptor neurons, the moist air and and the dry air neuron, respectively. Using extracellular single sensillum recording in the range of 20 to 45 °C it was shown that at temperatures above 25 (30) °C, firing mode of the DSSs neurons changes. They switch from regular spiking to spike bursting. Several parameters of the bursts of all the three neurons are temperature dependent and may hierarchically encode noxious heat up to lethal levels in a graded manner. According to their reaction type and response modality, the three DSS neurons were reclassified as the cold-hot neuron, the moist-hot neuron and the dry-hot neuron, respectively. The possible involvement of spike bursting in behavioural thermoregulation of the beetles is discussed. These findings consider spike bursting as general, fundamental quality of the classical sensory triad of insect antennal thermo- and hygro-thermoreceptor neurons being a flexible and reliable mode of coding unfavourably high temperatures.Vaatamata sellele, et temperatuur mõjutab kõiki eluslooduse tasandeid, on väga vähe andmeid selle kohta, kuidas tajuvad ohtlikult kõrgeid temperatuure ektotermid sh. putukad, mis on määrava tähtsusega nende käitumuslikus termoregulatsioonis ja ellujäämisel. Väga vähe on teada mil viisil kodeerivad ohtlikult kõrgeid temperatuure perifeersed temperatuuritundlikud neuronid. Käesolevas doktoritöös, kasutades uudset fokusseeritud ioonkiirte skanneeriva elektronmikroskoopia kombineeritud tehnikat, näidatakse, et põllumajanduslikult olulistel jooksiklastel ja naksurlastel paiknevad termo-ja hügroretseptorneuronid antennaalsetes kuppeljates sensillides (DSS), mis erinevad morfoloogiliselt putukate kõigist senituntud sensillitüüpidest. DSS innerveerib klassikaline neuronite triaad: külmaneuron ja kaks antagonistlikku hügroretseptorneuronit (niiske ja kuiva õhu neuron). Üksiku sensilli rakuväline registreerimine temperatuuri vahemikus 20 kuni 45 oC näitas, et temperatuuridel üle 25 (30 oC) lülituvad DSS neuronid regulaarsete närviimpulsside genereerimiselt impulssvalangute genereerimisele. Kõigi kolme neuroni mitmed valangulised parameetrid on temperatuurisõltuvuslikud ja võivad hierarhiliselt kodeerida ohtlikult kõrgeid temperatuure. Vastavalt sensoorsele modaalsusele ja reaktsiooni tüübile nimetati DSS paiknevad neuronid ümber külma-kuumaneuroniks ja õhuniiskuse-kuumaneuroniks ning õhukuivuse-kuumaneuroniks. Töö tulemused näitavad esmakordselt, et impulss-valangute genereerimise võime on putukate klassikalise termo- ja hügroneuronite triaadi üldine ja fundamentaalne omadus võimaldades paindlikult ja usaldusväärselt kodeerida kõrgeid temperatuure, mis on kriitilise tähtsusega ektotermide käitumuslikus termoregulatsioonis.Publication of this thesis is supported by the Estonian University of Life Sciences