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C. elegans (1,5,6,8/11) (C. elegans as an experimental organism (Simple…

- - - - Modularity
      - Small-worldness
      - Assortativity
      - Reciprocity
      - A trade-off between biological cost and functional value guides organization of neuronal networks. Over the course of evolutionary progress, these selection pressures may have led to or gradually progressed to a 'universally optimal organisation'
      - Rich club network organization
        
        High degree nodes (i.e. with many connections) are significantly more connected to each other. This is not solely a result of their intrinsic high degree nature as analysis of degree correlation showed that these 'rich club neurons' are more interconnected than chance expectation given their degree (Towlson et al., 2013)
        
        This form of rich cub organisation is conserved across a diverse range of nervous system scale (Van Heuvel & Sporns, 2011)
        
        However, the members of the rich club in human brains are cortical areas and not individual cells
        
        The C. elegans rich club
        
        Rich club corresponds to layer 3b premotor neurons: (AVA, AVD, AVE), (AVB, PVC)
        
        These gate forward or backward motor programs (Chalfie et al., 1985 w/ laser ablasion studies). Hence also called 'Command Interneurons'
        
        GECI studies show that neural activity of these interneurons correlate with forward (AVB, PVC) and backward (AVA, AVD, AVE) movements
        
        Optogenetic activation of AVA+AVD causes backward and activation of PVC causes forward acceleration. An important validation experiment
        
        However, rich club neurons make lots of connections not just to motor neurons but also other peripheral sensory neurons or interneurons suggesting a more global communication role of the premotor rich club to influence behaviour
    - - Analogous to an electrical circuit, stereotypic wiring of basic components may constitute a functional unit with a designated output
        
        Searching for over-represented neuronal microcircuits in neural systems of simple organisms can lead to the identification of functional units
        
        Feed-forward loop (Chemical synapses)
        
        Hub-and-spoke (Gap junctions)
        
        These synaptic motifs are also over-represented in the mammalian cortex (Song et al., 2005) suggesting a conserved feature between worm connectome and larger nervous systems
        
        One caveat however is to consider the units of the neuronal microcircuits as simple input-output units and not as individual processors themselves i.e. a neuronal circuit may be a circuit of neuronal circuits
      - Again, the same economical trade-off may have been instrumental in the evolution of microcircuits to conserve space, time, and material
  - - - ADE/CEP = Release monoamines & AVM = Release neuropeptides
      - For example, RIC neurons release octopamine which binds octopamine receptors expressed in a total of 26 neurons, all of which are extrasynaptic to RIC
    - - Reducibility analysis: Monoamine and peptide networks show little overlap with wired networks
      - Degree correlation: Extrasynaptic hubs are distinct from synaptic hubs
      - This variability allows for adaptive behaviour?
      - Distinct topological properties in connectome layers e.g. MA networks are highly assortative (edges join low degree nodes), NP networks are highly clustered, more integrated
    - - Even though extrasynaptic rich club is distinct from synaptic (wired) rich club, they two are still connected
        
        This significantly alters the functional connectome. MA and NP networks can bypass wired hubs in the premotor rich. This allows for modulation of motor pathways by sensory neurons
- - - - PVD
    - - ASH
    - - FLP
    - - AVM & ALM = anterior touch
      - PVM = posterior touch
  - - - Piggott et al. (2011): However, ablation of AVA/AVD does not eliminate escape reversals
        
        Extrasynaptic signalling
        
        AIB-RIM-dependent disinhibitory circuit
      - If you think about it, a nose touch escape response is bound to include a) head withdrawal and b) slowing
        
        OLQ/IL1 mediate head withdrawal
        
        CEP mediate slowing response
        
        All these cells (ASH, OLQ, CEP) respond to nose touch (constitute the cellular mechanism for nose touch escape behaviour) and require certain molecules to do so. (TRPA-1 in OLQ, TRP-4 in CEP, OSM-9 in ASH) This is evidence that specific molecules are required for observed nose touch response (the molecular mechanisms for nose touch behaviour)
  - - - Harsh head touch response requires cell-autonomous MEC-10, nose touch response requires OLQ-derived OSM-9
        
        How do non-autonomous contributions (e.g. OSM-9 acting in OLQ facilitating gentle touch response) arise?
        
        The role of electrical signalling in the escape circuit
        
        ~900 gap junctions in C. elegans connecting most neurons (White et al., 1986)
        
        Hub-and-spoke motif: OLQ is connected to FLP through electrically coupled hub-and-spoke network
        
        Evidence from Chatzigeorgiou & Schafer (2011)
        
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        The hub-and-spoke network acts as a coincidence detector allowing the primary sensory neuron - FLP - to integrate information from neighbouring mechanoreceptors - OLQ and CEP - and generate the appropriate response
        
        Shunting inhibition
        
        OLQ/CEP ablation does not affect noise touch avoidance due to shunting effects
        
        Silencing nose touch neurons (e.g. trp-4- in CEP) inhibits nose touch more than ablating the same neurons
        
        Strengthening gap junctions to silenced neurons also inhibits nose touch more (Rabinowitch et al., 2014)
        
        How does extrasynaptic signalling integrate with electrical signalling circuits to modulate movement behaviour?
        
        CEP is the primary DA releasing neuron. DA acts extrasynaptically to enhance escape-inducing sensory neurons
        
        Ezcurra et al. (2011): ASH-mediated escape behaviour (e.g. to copper) is enhanced with ChR2 activation of DA neurons
        
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        Kindt et al. (2007): With repeated tap stimulation, worm habituates and reversal diminishes. In the presence of food (bacteria lawn), the touch habituation effect is weakened.
        
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- - - - Klinokinesis: Modulation of turn probability in response to attractant or repellent
        
        C. elegans navigation can be broken down into periods of smooth swimming (runs) and periods of frequent pirouetting (turns). The pirouette model
        
        Pierce-Shimomura et al. (1999): The probability of taking a turn is most likely when worm moves down the concentration gradient (dC/dt < 0). In contrast, probability of turn is smallest when worm is heading up the concentration gradient (dC/dt > 0)
        
        ASE neurons (ASEL and ASER) are functionally asymmetric (due to asymmetric expression of rGCs?) as they are not linked by gap junctions
        
        Wired signalling. ON cell/OFF cell circuit allows precise detection of concentration changes (analogy with human retina)
        
        Contrary to escape behaviour, navigation behaviour is more unpredictable and 'random'
        
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        ASEL = ON cell. Stimulated in response to increasing salt concentration
        
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        ASER = OFF cell. Stimulated in response to decreasing salt concentration. Inhibited in response to increasing salt concentration
        
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        Rabinowitch et al. (2014): Electrically coupling ASER and ASEL leads to having 2 OFF cells, impairing chemotaxis but not abolishing it
      - Orthokinesis: Modulation of speed in response to attractant or repellent
        
        For example, food slowing behaviour
        
        Extrasynaptic signalling
        
        CEP are the primary release neurons for DA. DA is both necessary and sufficient for food slowing behaviour
        
        Chase et al. (2004)
        
        CEPs for mechanosensation of food
        
        Sawin et al. (2000)
        
        5-HT is also implicated in food slowing
        
        Sawin et al.(2000)
        
        Eczurra et al. (2011)
        
        ADF for chemosensation of food odours (Iwanir et al., 2016)
        
        CEPs mechanically sense the presence of food and release DA that transduces this mechanosensory stimuli to the motor circuits that will trigger slowing in locomotion. At the same time, the chemosensory system allows to track down distant food sources
      - Klinotaxis: Modulation of turn direction in response to attractant or repellent
        
        The turn direction is biased towards higher attractant concentration
        
        Considering amphid sensory neurons are so closely spaced, how can the worm sense spatial gradients?
        
        Head swings sample local concentration differences in the environment (Kato et al., 2014)
        
        Calcium compartmentalization in RIA: Local calcium transients correlate with dorsal and ventral turns
        
        The temporal correlation of sensory AIY and motor SMD inputs bias outputs to dorsal and ventral SMDs to mediate steering
        
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        High activity in nrD for dorsal head turn and high activity in nrV for ventral head turn