Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1ß, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.

Direct and indirect nigrofugal projections to the nucleus reticularis pontis caudalis mediate in the motor execution of the acoustic startle reflex.

The acoustic startle reflex (ASR) is a short and intense defensive reaction in response to a loud and unexpected acoustic stimulus. In the rat, a primary startle pathway encompasses three serially connected central structures: the cochlear root neurons, the giant neurons of the nucleus reticularis pontis caudalis (PnC), and the spinal motoneurons. As a sensorimotor interface, the PnC has a central role in the ASR circuitry, especially the integration of different sensory stimuli and brain states into initiation of motor responses. Since the basal ganglia circuits control movement and action selection, we hypothesize that their output via the substantia nigra (SN) may interplay with the ASR primary circuit by providing inputs to PnC. Moreover, the pedunculopontine tegmental nucleus (PPTg) has been proposed as a functional and neural extension of the SN, so it is another goal of this study to describe possible anatomical connections from the PPTg to PnC. Here, we made 6-OHDA neurotoxic lesions of the SN pars compacta (SNc) and submitted the rats to a custom-built ASR measurement session to assess amplitude and latency of motor responses. We found that following lesion of the SNc, ASR amplitude decreased and latency increased compared to those values from the sham-surgery and control groups. The number of dopamine neurons remaining in the SNc after lesion was also estimated using a stereological approach, and it correlated with our behavioral results. Moreover, we employed neural tract-tracing techniques to highlight direct projections from the SN to PnC, and indirect projections through the PPTg. Finally, we also measured levels of excitatory amino acid neurotransmitters in the PnC following lesion of the SN, and found that they change following an ipsi/contralateral pattern. Taken together, our results identify nigrofugal efferents onto the primary ASR circuit that may modulate motor responses.

Relations between Sensorimotor Integration and Speech Disorders in Parkinson's Disease.

BACKGROUND: Sensorimotor integration mechanisms can be affected by many factors, among which are those involving neuromuscular disorders. Parkinson's disease (PD) is characterized by well-known motor symptoms, among which lately have been included motor speech deficits. Measurement of the acoustic startle reflex (ASR) and its modulations (prepulse inhibition and prepulse facilitation, PPI and PPF respectively) represent a simple and quantifiable tool to assess sensorimotor function. However, it remains unknown whether measures of the PPI and PPF are associated with motor speech deficits in PD. METHODS: A total of 88 subjects participated in this study, 52 diagnosed with PD and 36 control subjects. After obtaining written informed consent, participants were assessed with PPI at several interstimulus intervals, and PPF at 1000 ms using the SRH-Lab system (San Diego, CA). Percentage of change in the amplitude and latency of the ASR was analyzed between groups. Voice recordings were register of a specific text given to the subjects with a professional recorder and temporal patterns of speech were analyzed. RESULTS: Statistical analysis conducted in this study showed differences in PPI and PPF in subjects with PD compared to controls. In addition, discriminative parameters of voice abnormalities were observed in PD subjects related to control subjects showing a reduction in phonation time, vowel pulses, breaks, breakage and voice speech periods. CONCLUSIONS: PD presents a disruption in sensorimotor filter mechanisms and speech disorders, and there is a relationship between these alterations. The correlation between the PPI and PPF with an alteration of the voice in PD subjects contributes toward understanding mechanism underlying the neurophysiological alterations in both processes. Overall, easy and non-invasive tests such as PPI, PPF together with voice analysis may be useful to identify early stages of PD.

Lymphoma outbreak in a GASH:Sal hamster colony.

We have detected a high incidence of lymphomas in a colony of GASH:Sal Syrian golden hamsters (Mesocricetus auratus). This strain is characterised by its ability to present convulsive crises of audiogenic origin. Almost 16 % (90 males and 60 females) of the 975 animals were affected during a 5-year period by the development of a progressing lymphoid tumour and exhibited similar clinical profiles characterised by lethargy, anorexia, evident abdominal distension, and a rapid disease progression resulting in mortality within 1 to 2 weeks. A TaqMan® probe-based real-time PCR analysis of genomic DNA from different tissue samples of the affected animals revealed the presence of a DNA sequence encoding the hamster polyomavirus (HaPyV) VP1 capsid protein. Additionally, immunohistochemical analysis using HaPyV-VP1-specific monoclonal antibodies confirmed the presence of viral proteins in all hamster tumour tissues analysed within the colony. An indirect ELISA and western blot analysis confirmed the presence of antibodies against the VP1 capsid protein in sera, not only from affected and non-affected GASH:Sal hamsters but also from control hamsters from the same breeding area. The HaPyV genome that accumulated in tumour tissues typically contained deletions affecting the noncoding regulatory region and adjacent sequences coding for the N-terminal part of the capsid protein VP2.

Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters.

Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet. Here, we show that Vav3 is expressed in GABAegic neurons of the ventrolateral medulla (VLM), a brainstem area that modulates respiratory rates and, via sympathetic efferents, a large number of physiological circuits controlling blood pressure. On Vav3 loss, GABAergic cells of the caudal VLM cannot innervate properly their postsynaptic targets in the rostral VLM, leading to reduced GABAergic transmission between these two areas. This results in an abnormal regulation of catecholamine blood levels and in improper control of blood pressure and respiration rates to GABAergic signals. By contrast, the reaction of the rostral VLM to excitatory signals is not impaired. Consistent with those observations, we also demonstrate that Vav3 plays important roles in axon branching and growth cone morphology in primary GABAergic cells. Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates.

Long-term functional recovery in the rat auditory system after unilateral auditory cortex ablation.

CONCLUSIONS: An intact bilateral auditory corticofugal projection is necessary for the auditory system, and above all its main targets, to start working correctly after an acoustic stimulation. After restricted unilateral cortical lesions, the auditory system is able to recover its function in adult animals at 90 days after surgery. (Post-lesion plasticity in adults.) OBJECTIVES: To study the influence of the cortex on the auditory system functionality and to asses its ability for post-lesion recovery. METHODS: Restricted unilateral lesions were made in the auditory cortex of adult rats. To evaluate the functionality of the auditory pathway after corticofugal deafferentation, the acoustic startle reflex and prepulse inhibition, together with the auditory brainstem response (ABR), were tested along the survival time. RESULTS: All the three tests showed a decrease in their responses at 15 days post lesion, and a full recovery at 90 days post lesion for the ABR and at 180 days post lesion for the acoustic startle reflex and prepulse inhibition.

Morphologic and neurochemical alterations in the superior colliculus of the genetically epilepsy-prone hamster (GPG/Vall).

The GPG/Vall hamster is an animal model that exhibits seizures in response to sound stimulation. Since the superior colliculus (SC) is implicated in the neuronal network of audiogenic seizures (AGS) in other forms of AGS, this study evaluated seizure-related anatomical or neurochemical abnormalities in the SC of the GPG/Vall hamster. This involved calbindin (CB) and parvalbumin (PV) immunohistochemistry, densitometric analysis and high performance liquid chromatography in the superficial and deep layers of the SC in control and epileptic animals. Compared to control animals, a reduction in SC volume and a hypertrophy of neurons located in the deep layers of the SC were observed in the epileptic hamster. Although, analysis of CB-immunohistochemistry in the superficial layers did not show differences between groups, analysis of PV-immunostaining in the deep SC revealed an increase in the mean gray level within immunostained neurons as well as a decreased immunostained neuropil in the GPG/Vall hamster as compared to control animals. These alterations were accompanied by a decrease in the levels of GABA and increased levels of taurine in the epileptic animal. These data indicate that the deep SC of the GPG/Vall hamster is structurally abnormal; suggesting its involvement in the neuronal network for AGS.