Friday, November 9, 2012

Two papers about cellular mechanisms for prepulse inhibition studied in Tritonia

 
A cellular mechanism for prepulse inhibition (2003)
by William N. Frost, Li-Ming Tian, Travis A. Hoppe, Donna L. Mongeluzi, and Jean Wang

This paper shows the first cellular-level evidence for prepulse inhibition in Tritonia. A weak sensory stimulus has both excitatory and inhibitory effects on S-cells. The inhibitory effects shunt the synaptic output of some S-cells.

Prepulse inhibition (PPI):
Strong, unexpected stimuli elicit startle responses in all animals, but it can be markedly attenuated if closely preceded by a weak stimulus. 
Schizophrenics show abnormally low level of PPI.

Tritonia PPI
A prepulse stimulus was given by vibrated stick before an electric shock to elicit the swim

The prepulse acts to hyperpolarize two cell types in the swim circuit
Tactile stimuli hyperpolarized DSI and S-cells, but it also cause a lot of excitatory responses in other neurons.

The prepulse shortens and narrows the S cell action potential
Spike narrowing seen in the S cell AP.

Identification of a neuron, Pl 9, mediating the prepulse-elicited S cell inhibition
Pl 9 appears to receive direct EPSPs from most or all ipsilateral S cells and inturn produces direct IPSPs bilaterally onto the entire S cell population, as well as onto the Tr1, DRI, and VSI-B interneurons.
Pl 9 mediates prepulse-elicited hyperpolarizing inhibition of the S cells.

Evidence that Pl 9 mediates PPI
Intracellular stimulation of a single Pl 9 blocked the swim motor program.
Killing a single Pl 9 reduced PPI

Pl 9 inhibits S cell synaptic efficacy
S cell-evoked EPSPs in the swim network neurons were reduced in size when S cells were activated. 

Pl 9 reduces S cell synaptic efficacy via presynaptic inhibition of S cell transmitter release
Pl 9-evoked IPSPs are mediated by Chloride ion, blocked by d-tubocurarine
Pl 9 caused reduction of presynaptic action potentials of S cells in duration and amplitude
The S cell synaptic efficacy depended on its membrane potential

Identification of a neuron, Pl 10, involved in prespulse-elicite postsynaptic inhibition of the DSIs
PI 9 had no direct contact onto DSI, but Pl 10 does.
Pl 10 can block the swim



This study above looking at change in synaptic efficacy of S cells
The next study then looked at change in spike propagation




Axonal conduction block as a novel mechanism of prepulse inhibition
by Anne H. Lee, Evgenia V. Megalou, Jean Wang, and William N. Frost

Prepulse nerve stimuli produce PPI of the swim motor program, and conduction block of S-cell action potential trains
PdN3 alone (swim) vs PdN3 preceded by CN1,4,5 (prepulse) - in all cases CN1,4,5 stim prevented the swim.
Stim of CN1,4,5 caused conduction failure of S-cells evoked by PdN3 stim
Sometimes saw incomplete blockade

Prepulse-elicited conduction block has the temporal features of behavioral PPI in Tritonia
Conduction failure seen when stim was given with 250-500 ms latency (stim, 400 ms)

Conduction block also occurs in response to skin prepulse

Evidence that interneuron Pl-9 mediates PPI of S-cell conduction block
Peak Pl firing was 43 and 59 Hz in response to the tactile stimulation
photoinnactivation of Pl-9 blocked PPI





Monday, November 5, 2012

Variability, compensation and homeostasis in neuron and network function




Eve Marder and Jean-Marc Goaillard

Hebbian learning can be appropriately balanced by stability mechanisms that allow neurons and synaptic connections to be maintained in appropriate operating ranges (by Turrigiano and Nelson, various mechanisms including synaptic scaling and changes in individual ionic currents).

omeostatic tuning rules that maintain a constant activity pattern could, in principle, operate to tune conductances so that an individual neuron remains within a given region of parameter space, although its values for one or more conductances may be substantially
altered.

Variability in channel densities
How can we reconcile the apparent sensitivity of many neurons to rapid pharmacological treatments with new data indicating that individual neurons within a class can differ by as much as two- to fourfold in the densities of many of their currents?
Computational models show that a number of different compensating combinations of conductances can result in similar activity patterns38,51.

In contrast to pharmacological manipulations, slow mechanisms that function during development and over days and weeks can result in a set of compensating conductances that give rise to a target activity pattern.

Figure 2 | Neurons with similar intrinsic properties have different ratios of conductances.

Figure 3 | Comparison of short-term pharmacological manipulations and long-term genetic deletions.

Slow developmental and homeostatic mechanisms can ‘find’ multiple solutions of correlated
and compensating values of membrane conductances consistent with a given activity pattern, even while rapid pharmacological treatments that vary the value of one current at a time result in altered activity57.


Recovery of Locomotion After Spinal Cord Injury: Some Facts and Mechanisms




Serge Rossignol and Alain Frigon

The model provide...The model has...This model produces...How this model can be approached...What can we learn from it.
This study focuses on...by first describing...Specifically we here show...We propose that...
First figure explains the system we study...How the system functions...We first describe the effects of a procedure...We then discuss the effects of...to establish new interactions for the generation of hindlimb locomotion.

LOCOMOTOR RECOVERY AFTER COMPLETE SPINAL TRANSECTION

Cats with a complete SCI (i.e., spinalization) at the last thoracic segment (T13) gradually recover hindlimb locomotion on a treadmill following a few weeks of locomotor training.

The Inescapable Central Spinal Pattern Generator

In acutely spinalized and paralyzed cats, fictive locomotion can be recorded with pharmacological stimulation (L-DOPA) in the complete absence of overt movement (Grillner & Zangger 1979).
In chronic spinal cats, fictive locomotion can occur spontaneously without drugs, indicating that functional changes have occurred within the spinal locomotor circuitry enabling the spontaneous expression of this endogenous pattern (Pearson & Rossignol 1991).

Functional organization of locomotorgenerating circuits.
The mammalian locomotor CPG is thought to be composed of interconnected modules that coordinate activity around specific joints (Grillner 1981). A multilayered spinal locomotor CPG, in which rhythm-generation and pattern formation are functionally separated, has been proposed to account for some experimental findings (reviewed in McCrea & Rybak 2008).

Spinal localization of locomotor-generating circuits.
For instance, although rhythmogenic properties within the lumbosacral spinal cord are somewhat distributed over several segments, the L3-L4 segments in cats (Marcoux & Rossignol 2000, Langlet et al. 2005, Delivet-Mongrain et al. 2008) and L1-L2 segments in rodents (Cazalets et al. 1995, Kiehn 2006) are critical for rhythm generation. This segmental
heterogeneity has important implications for the recovery of walking after SCI.

A balance between excitation and inhibition.
Function within the spinal locomotor network is governed by excitatory and inhibitory connections. During locomotion, motoneurons receive rhythmic alternating pushpull patterns of glutamatergic excitation and glycinergic inhibition during the active and inactive phases, respectively (Shefchyk & Jordan 1985, Cazalets et al. 1996, Grillner 2003). Excitatory connections are sufficient to drive rhythmic bursting because blocking inhibitory transmission, through GABAA (i.e., bicuculline) and glycine (i.e., strychnine) receptor antagonists, does not abolish oscillatory activity (Kjaerulff & Kiehn 1997, Grillner & Jessell 2009). However, inhibition is necessary to produce appropriate flexion/extension (Cowley & Schmidt 1995) and left-right (Cowley & Schmidt 1995, Kremer & Lev-Tov 1997, Hinckley et al. 2005) alternations (Grillner &Jessell 2009).

Intrinsic properties of central pattern generator neurons.
voltage-dependent persistent inward currents (PICs) that amplify excitatory synaptic inputs and sustain neuronal firing are thought to facilitate rhythmogenesis by timing and shaping locomotor output (Brownstone et al. 1994, Kiehn et al. 1996, Tazerart et al. 2008).

Cellular changes in spinal locomotorgenerating circuits.
Immediately after SCI, the excitability of spinal interneurons and motoneurons is depressed because of the loss of excitatory neuromodulatory inputs from brainstem-derived pathways. The return of neuronal excitability is required for functional recovery and can be mediated by several factors.
Some 5-HT receptors became constitutively active following SCI in adult rats, indicating that intracellular signaling occurred without normal ligand binding. Some receptors can also become supersensitive to remaining endogenous sources of neurotransmitters.
Changes in inhibitory circuits could also play a part in modifying neuronal excitability following SCI; increased levels of inhibitory neurotransmitters (i.e., more inhibition) could depress neuronal excitability and impair specific spinal circuits.
The switch from inhibition to facilitation in adult rats was partly attributed to downregulation of potassiumchloride cotransporter 2 (KCC2) in lumbar neurons (Boulenguez et al. 2010, Boulenguez & Vinay 2009). KCC2 expression progressively decreased within the ventral horn following complete or incomplete SCI, and increased levels of intracellular Cl− diminished the efficacy of synaptic inhibition.

The Key Role Played by Sensory Inputs

Sensory inputs play a key role in the regulation of normal locomotion, which can be altered after SCI. After complete SCI, intrinsic changes at the cellular level of the CPG promote the return of hindlimb locomotion through interactions with peripheral sensory inputs.

Spinal reflexes during locomotion.
Reflex responses are state- and phase-dependent, indicating that sensory processing is regulated by context or, in other words, the current configuration of the spinal circuitry.
Changes at the cellular level following SCI will directly impact the regulation of peripheral sensory inputs and their interaction with the spinal locomotor CPG.

Changes in spinal reflexes after spinal lesion.
If a small portion of sensory feedback is reduced by lesioning specific peripheral nerves before a complete SCI in adult cats, the recovery of hindlimb locomotion is severely impaired.

LOCOMOTOR RECOVERY AFTER PARTIAL SPINAL LESIONS

After incomplete SCI, spared pathways originating from supraspinal and propriospinal structures can play an active role in the recovery process, and also in restoring some voluntary
control. However, intrinsic spinal circuits and peripheral afferents still remain to initiate and
organize hindlimb locomotion.

Accessing the Locomotor Circuitry by Descending Inputs

Ventral and ventrolateral lesions (reticulospinal and vestibulospinal pathways).

Dorsal/dorsolateral lesions (corticospinal and rubrospinal pathways).

Other pathways.
Propriospinal pathways. Propriospinal pathways appear to be of considerable importance for volitional aspects of locomotor recovery.Noradrenergic and serotonergic pathways. The loss of neurotransmitters will in turn
have important consequences on themembran properties of target neurons
.

Multiple pathways severed by contusions or hemisections.
Contusions. Locomotor recovery did not depend on the sparing of corticospinal or long propriospinal pathways (Basso et al. 1996), indicating a role for short intraspinal circuits.
Hemisections.

Mechanisms of Locomotor Recovery After Partial Spinal Cord Injury

Intrinsic spinal mechanisms and afferent mechanisms are still critical in locomotor recovery after an incomplete SCI. In turn, new interactions can modify spared structures throughout the CNS, not just the spinal cord.
Functional recovery is often thought to result from a combination of regeneration, sprouting, or other ill-defined plastic changes in descending pathways (Cafferty et al. 2008).

Compensation by sensory afferents.
Sprouting of sensory afferents on the lesioned side is prominent and could partly account for the functional recovery of various motor patterns (Goldberger 1977, Helgren & Goldberger 1993).
Sensory feedback is of crucial importance in the recovery process.

Compensation by descending pathways.
New circuits could result from new anatomical connections (new circuits) or from enhanced connectivity(enhancing existing circuits).

Regeneration and sprouting. There is a lack of hard evidence that regenerated lesioned axons induce significant functional improvements because of the small number of regenerating axons.
A critical question is whether regenerated fibers are even functional.
Experiments using staggered spinal hemisections show that the regeneration of long descending pathways is not necessary (Kato 1989).
Locomotor recovery depends more on intrinsic spinal mechanisms and contributions from sensory afferents.

New/old circuits. There is no doubt that the propriospinal systems (long and short) can reach the CPG.
The recovery of hindlimb locomotion after a complete SCI in cats, rats, and mice absolutely requires a spinal circuitry capable of generating the basic locomotor pattern independently of descending commands (Grillner 1981; Rossignol 1996, 2006; Rossignol et al. 2006).

Compensation by the Intrinsic Spinal Circuitry. Recent work on the escape swim of a mollusc (Tritonia diomedea) showed near immediate changes within the functional connectivity of the swim CPG following a lesion within the intrinsic circuitry that compensated for the loss of long projections and reinstated function in the absence of regeneration (Sakurai&Katz 2009). A considerable portion of the recovery could be mediated within spinal circuits rather than by a functional takeover by descending pathways.
We propose that the recovery of function by descending or afferent inputs after SCI essentially depends on how the circuitry has adapted to the total or partial absence of descending inputs.

IMPLICATIONS FOR HUMANS WITH SPINAL CORD INJURY