Role of synchronous activation of cerebellar purkinje cell ensembles in multi-joint movement control

It is a longstanding question in neuroscience how elaborate multi-joint movements are coordinated coherently. Microzones of cerebellar Purkinje cells (PCs) are thought to mediate this coordination by controlling the timing of particular motor domains. However, it remains to be elucidated to what extent motor coordination deficits can be correlated with abnormalities in coherent activity within these microzones and to what extent artificially evoked synchronous activity within PC ensembles can elicit multi-joint motor behavior. To study PC ensemble correlates of limb, trunk, and tail movements, we developed a transparent disk treadmill that allows quantitative readout of locomotion and posture parameters in head-fixed mice and simultaneous cellular-resolution imaging and/or optogenetic manipulation. We show that PC ensembles in the ataxic and dystonic mouse mutant tottering have a reduced level of complex spike co-activation, which is delayed relative to movement onset and co-occurs with prolonged swing duration and reduced phase coupling of limb movements as well as with enlarged deflections of body-axis and tail movements. Using optogenetics to increase simple spike rate in PC ensembles, we find that preferred locomotion and posture patterns can be elicited or perturbed depending on the behavioral state. At rest, preferred sequences of limb movements can be elicited, whereas during locomotion, preferred gait-inhibition patterns are evoked. Our findings indicate that synchronous activation of PC ensembles can facilitate initiation and coordination of limb and trunk movements, presumably by tuning downstream systems involved in the execution of behavioral patterns

Anticipatory grip force control using a cerebellar model.

Grip force modulation has a rich history of research, but the results remain to be integrated as a neurocomputational model and applied in a robotic system. Adaptive grip force control as exhibited by humans would enable robots to handle objects with sufficient yet minimal force, thus minimizing the risk of crushing objects or inadvertently dropping them. We investigated the feasibility of grip force control by means of a biological neural approach to ascertain the possibilities for future application in robotics. As the cerebellum appears crucial for adequate grip force control, we tested a computational model of the olivo-cerebellar system. This model takes into account that the processing of sensory signals introduces a 100 ms delay, and because of this delay, the system needs to learn anticipatory rather than feedback control. For training, we considered three scenarios for feedback information: (1) grip force error estimation, (2) sensory input on deformation of the fingertips, and (3) as a control, noise. The system was trained on a data set consisting of force and acceleration recordings from human test subjects. Our results show that the cerebellar model is capable of learning and performing anticipatory grip force control closely resembling that of human test subjects despite the delay. The system performs best if the delayed feedback signal carries an error estimation, but it can also perform well when sensory data are used instead. Thus, these tests indicate that a cerebellar neural network can indeed serve well in anticipatory grip force control not only in a biological but also in an artificial system

Climbing fiber burst size and olivary sub-threshold oscillations in a network setting.

textabstractThe inferior olivary nucleus provides one of the two main inputs to the cerebellum: the so-called climbing fibers. Activation of climbing fibers is generally believed to be related to timing of motor commands and/or motor learning. Climbing fiber spikes lead to large all-or-none action potentials in cerebellar Purkinje cells, overriding any other ongoing activity and silencing these cells for a brief period of time afterwards. Empirical evidence shows that the climbing fiber can transmit a short burst of spikes as a result of an olivary cell somatic spike, potentially increasing the information being transferred to the cerebellum per climbing fiber activation. Previously reported results from in vitro studies suggested that the information encoded in the climbing fiber burst is related to the occurrence of the spike relative to the ongoing sub-threshold membrane potential oscillation of the olivary cell, i.e. that the phase of the oscillation is reflected in the size of the climbing fiber burst. We used a detailed three-compartmental model of an inferior olivary cell to further investigate the possible factors determining the size of the climbing fiber burst. Our findings suggest that the phase-dependency of the burst size is present but limited and that charge flow between soma and dendrite is a major determinant of the climbing fiber burst. From our findings it follows that phenomena such as cell ensemble synchrony can have a big effect on the climbing fiber burst size through dendrodendritic gap-junctional coupling between olivary cells

Immunomodulation of the melanoma sentinel lymph node: A novel adjuvant therapeutic option

Cutaneous melanoma is the most aggressive type of skin cancer. Paradoxically, melanoma is also the most immunogenic tumour identified to date: tumour-reactive T cells are detectable both in the blood and in tumour-draining lymph nodes (TDLN) of melanoma patients and their frequency can be increased by specific vaccination. However, early melanoma development is accompanied by impaired immune effector functions in the initial TDLN, the sentinel lymph node (SLN). Most notably, a reduced frequency and activation state of dendritic cells (DC) interferes with the uptake and presentation of tumour-associated antigens (TAA) to specific anti-tumour cytotoxic T-lymphocytes (CTL) and T helper cells (Th). These impaired immune effector functions may contribute to the early metastatic events that are associated with this tumour type. Since complete surgical excision at an early stage remains the only curative treatment option (adjuvant therapy options are limited and show no survival benefits), immunopotentiation of the SLN to jump-start or boost tumour specific immunity in early stage melanoma may be a valuable adjuvant treatment option that can be generally applied with minimal discomfort to the patient. Early clinical studies indicate that local Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF) or Cytosine-phosphate-Guanine (CpG) administration leads to activation of different DC subsets and conditions the SLN microenvironment to be more conducive to the generation of T-cell-mediated anti-tumour immunity

Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients

Purpose: A decrease in the frequency and activation state of dendritic cells in the sentinel lymph node (SLN) has been observed in early stages of melanoma development. This may hinder the generation of effective antitumor T-cell responses and increase the likelihood of metastatic spread. Immunopotentiation of the melanoma SLN may therefore be a valuable adjuvant treatment option. One way to achieve this is through the use of bacterially derived unmethylated cytosine-phosphate-guanine (CpG) DNA sequences that bind Toll-like receptor 9 and activate plasmacytoid dendritic cells (PDC). CpG-activated PDC, in turn, release IFNα and may thus boost T-cell and natural killer cell responses as well as activate conventional myeloid dendritic cells (MDC). Experimental Design: We studied the effects of preoperative local administration of the CpG B-type oligodeoxynucleotide (ODN) PF-3512676 (formerly known as CPG 7909) on dendritic cell and T-cell subsets in the SLN of 23 stage I to III melanoma patients, randomized to receive intradermal injections of either PF-3512676 or saline (NaCl 0.9%). Results: PF-3512676 administration resulted in bulkier SLN, higher yields of isolated SLN leukocytes, and activation of BDCA-2+CD123+ PDC as well as of CD1a + MDC. In addition, PF-3512676 administration was associated with the presence of a newly identified CD11chi CD123+CD83 +TRAIL+ mature SLN-MDC subset, an increased release of a variety of inflammatory cytokines, and lower frequencies of CD4 +CD25hiCTLA-4+FoxP3+ regulatory T cells in the SLN. Conclusions: These findings point to the possible utility of the conditioning of SLN by PF-3512676 as an adjuvant immunotherapeutic modality for early-stage melanoma