Frequency dependence of behavioral modulation by hippocampal electrical stimulation.

Electrical stimulation offers the potential to develop novel strategies for the treatment of refractory medial temporal lobe epilepsy. In particular, direct electrical stimulation of the hippocampus presents the opportunity to modulate pathological dynamics at the ictal focus, although the neuroanatomical substrate of this region renders it susceptible to altering cognition and affective processing as a side effect. We investigated the effects of three electrical stimulation paradigms on separate groups of freely moving rats (sham, 8-Hz and 40-Hz sine-wave stimulation of the ventral/intermediate hippocampus, where 8- and 40-Hz stimulation were chosen to mimic naturally occurring hippocampal oscillations). Animals exhibited attenuated locomotor and exploratory activity upon stimulation at 40 Hz, but not at sham or 8-Hz stimulation. Such behavioral modifications were characterized by a significant reduction in rearing frequency, together with increased freezing behavior. Logistic regression analysis linked the observed changes in animal locomotion to 40-Hz electrical stimulation independently of time-related variables occurring during testing. Spectral analysis, conducted to monitor the electrophysiological profile in the CA1 area of the dorsal hippocampus, showed a significant reduction in peak theta frequency, together with reduced theta power in the 40-Hz vs. the sham stimulation animal group, independent of locomotion speed (theta range: 4-12 Hz). These findings contribute to the development of novel and safe medical protocols by indicating a strategy to constrain or optimize parameters in direct hippocampal electrical stimulation.

The VGF-derived peptide TLQP-21: a new modulatory peptide for inflammatory pain.

Vgf, is a neuro-endocrine specific gene encoding for a large protein precursor of different peptides. A role for VGF in pain modulation has been suggested from immunohistochemical studies showing VGF mRNA widely expressed in primary sensory neurons. In this study, the presence of VGF on the primary sensory afferents in mice was confirmed by showing its immunostaining in cultured neurons of dorsal root ganglia in secretory granule varicosities colocalized with Substance P. Moreover, the functional role of a C-terminal internal VGF-derived peptide, i.e. TLQP-21, was assessed by investigating its peripheral (1, 2, 4, 8mM) and central (1, 2, 4 mM) effects on inflammatory pain in the formalin test. A significant increase of pain-related licking response following peripheral injection of TLQP-21 (4 and 8mM) was observed in the second inflammatory phase of the test. In addition, an increase in licking response was detected when 4 mM of the peptide was injected alone without formalin. On the other hand, the central administration of TLQP-21 induced an U-shaped curve, with the dose of 2 mM being analgesic during the second phase. This study shows for the first time that a VGF-derived peptide may be involved in inflammatory pain in vivo and demonstrates a different action for TLQP21 at the peripheral and central levels of the nociceptive pathways.

Differential expression and seasonal modulation of VGF peptides in sheep pituitary.

The inducible gene vgf and its peptide products are relevant to the neuroendocrine regulation of homeostasis and reproduction in rodents. We show here that in the anterior pituitary of female sheep the somatotrope, gonadotrope, and lactotrope/thyrotrope cell populations each expressed vgf mRNA, but displayed a distinct profile of VGF immunoreactive peptides. ProVGF C-terminus and VGF(443-588) immunoreactivities were found in lactotropes and thyrotropes, often in a subcellular location restricted to the Golgi area and suggestive of rapid peptide (or proVGF) release upon biosynthesis, while high molecular weight bands consistent with proVGF were shown in pituitary extracts. Distinct seasonal changes were revealed, proVGF C-terminus immunoreactive cells being largely identified as lactotropes during the summer (83.7 +/- 2.1% (mean +/-s.e.m.) versus 27.0 +/- 1.9% during the winter), as opposed to thyrotropes during the winter (73.0 +/- 1.9% versus 16.3 +/- 2.1% during the summer). Conversely, antisera to peptides adjacent to the 'Arg-Pro-Arg' cleavage site, and to the VGF(553-555) N-terminus of the proVGF-derived peptide V, selectively labeled gonadotropes, indicating processing to small peptides not retaining the proVGF C-terminus in such cells. Finally, a peptide related to the VGF(4-240) region was immunostained in somatotropes, shown in a Western blot as a band of relative molecular mass of approximately 16,000. In conclusion, a complex, endocrine cell-type-specific processing of proVGF was revealed. Further to the known inducibility of vgf mRNA upon a range of stimuli, discreet, selective modulations of VGF-peptide profile/s are suggested, possibly involved in specific neuro/endocrine or modulatory mechanisms.