Roberto Panichi

Distinct determinants of sparse activation during granule cell maturation.

Adult neurogenesis continually produces a small population of immature granule cells (GCs) within the dentate gyrus. The physiological properties of immature GCs distinguish them from the more numerous mature GCs and potentially enables distinct network functions. To test how the changing properties of developing GCs affect spiking behavior, we examined synaptic responses of mature and immature GCs in hippocampal slices from adult mice. Whereas synaptic inhibition restricted GC spiking at most stages of maturation, the relative influence of inhibition, excitatory synaptic drive, and intrinsic excitability shifted over the course of maturation. Mature GCs received profuse afferent innervation such that spiking was suppressed primarily by inhibition, whereas immature GC spiking was also limited by the strength of excitatory drive. Although the input resistance was a reliable indicator of maturation, it did not determine spiking probability at immature stages. Our results confirm the existence of a transient period during GC maturation when perforant path stimulation can generate a high probability of spiking, but also reveal that immature GC excitability is tempered by functional synaptic inhibition and reduced excitatory innervation, likely maintaining the sparse population activity observed in vivo.

ERG voltage-gated K+ channels regulate excitability and discharge dynamics of the medial vestibular nucleus neurones

The discharge properties of the medial vestibular nucleus neurones (MVNn) critically depend on the activity of several ion channel types. In this study we show, immunohistochemically, that the voltage‐gated K+ channels ERG1A, ERG1B, ERG2 and ERG3 are highly expressed within the vestibular nuclei of P10 and P60 mice. The role played by these channels in the spike‐generating mechanisms of the MVNn and in temporal information processing was investigated electrophysiologically from mouse brain slices, in vitro, by analysing the spontaneous discharge and the response to square‐, ramp‐ and sinusoid‐like intracellular DC current injections in extracellular and whole‐cell patch‐clamp studies. We show that more than half of the recorded MVNn were responsive to ERG channel block (WAY‐123,398, E4031), displaying an increase in spontaneous activity and discharge irregularity. The response to step and ramp current injection was also modified by ERG block showing a reduction of first spike latency, enhancement of discharge rate and reduction of the slow spike‐frequency adaptation process. ERG channels influence the interspike slope without affecting the spike shape. Moreover, in response to sinusoid‐like current, ERG channel block caused frequency‐dependent gain enhancement and phase‐lead shift. Taken together, the data demonstrate that ERG channels control the excitability of MVNn, their discharge regularity and probably their resonance properties.

Improvement of Stance Control and Muscle Performance Induced by Focal Muscle Vibration in Young-Elderly Women: A Randomized Controlled Trial

UNLABELLED Filippi GM, Brunetti O, Botti FM, Panichi R, Roscini M, Camerota F, Cesari M, Pettorossi VE. Improvement of stance control and muscle performance induced by focal muscle vibration in young-elderly women: a randomized controlled trial. OBJECTIVE To determine the effect of a particular protocol of mechanical vibration, applied focally and repeatedly (repeated muscle vibration [rMV]) on the quadriceps muscles, on stance and lower-extremity muscle power of young-elderly women. DESIGN Double-blind randomized controlled trial; 3-month follow-up after intervention. SETTING Human Physiology Laboratories, University of Perugia, Italy. PARTICIPANTS Sedentary women volunteers (N=60), randomized in 3 groups (mean age +/- SD, 65.3+/-4.2y; range, 60-72). INTERVENTION rMV (100Hz, 300-500microm, in three 10-minute sessions a day for 3 consecutive days) was applied to voluntary contracted quadriceps (vibrated and contracted group) and relaxed quadriceps (vibrated and relaxed group). A third group received placebo stimulation (nonvibrated group). MAIN OUTCOME MEASURES Area of sway of the center of pressure, vertical jump height, and leg power. RESULTS Twenty-four hours after the end of the complete series of applications, the area of sway of the center of pressure decreased significantly by approximately 20%, vertical jump increased by approximately 55%, and leg power increased by approximately 35%. These effects were maintained for at least 90 days after treatment. CONCLUSIONS rMV is a short-lasting and noninvasive protocol that can significantly and persistently improve muscle performance in sedentary young-elderly women.

Prolonged asymmetric vestibular stimulation induces opposite, long‐term effects on self‐motion perception and ocular responses

•  The semicircular canals of the labyrinths are a source of information for self‐motion perception and reflex eye movements. •  Prolonged vestibular asymmetric stimulation of standing humans about the earth‐vertical axis, made of fast body rotation to one side and slow rotation to the other side, induced different adaptive mechanisms in the perception of body motion and in the vestibulo‐ocular reflex (VOR). •  Motion perception became progressively more asymmetric, increasing gradually in response to the fast body rotation and decreasing in response to the slow rotation. VOR became gradually more symmetric, decreasing for fast body movement and increasing for slow movement. •  These oppositely directed adaptive effects in motion perception and VOR persisted for at least 30 min. •  Long‐lasting asymmetric stimulation discloses independent brain mechanisms for perception of body motion and eye movement control. •  These adaptive mechanisms may enhance awareness toward the side where the body is moving faster, while improving eye stabilizing properties of the VOR.

Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats

Estrogenic and androgenic neurosteroids can rapidly modulate synaptic plasticity in the brain through interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used electrophysiological recordings in slices of young and adolescent male rats to explore the influence of sex neurosteroids on synaptic plasticity in the CA1 hippocampal region, by blocking ARs or ERs during induction of long‐term depression (LTD) and depotentiation (DP) by low‐frequency stimulation (LFS) and long‐term potentiation (LTP) by high‐frequency stimulation (HFS). We found that LTD and DP depend on ARs, while LTP on ERs in both age groups. Accordingly, the AR blocker flutamide affected induction of LTD reverting it into LTP, and prevented DP, while having no effect on HFS‐dependent LTP. Conversely, ER blockade with ICI 182,780 (ICI) markedly reduced LTP, but did not influence LTD and DP. However, the receptor blockade did not affect the maintenance of either LTD or LTP. Moreover, we found that similar to LTP and LTD induced in control condition, the LTP unveiled by flutamide during LFS and residual LTP induced by HFS under ICI depended on N‐methyl‐d aspartate receptor (NMDAR) activation. Furthermore, as the synaptic paired‐pulse facilitation (PPF) was not affected by either AR or ER blockade, we suggest that sex neurosteroids act primarily at a postsynaptic level. This study demonstrates for the first time the crucial role of estrogenic and androgenic neurosteroids in determining the sign of hippocampal synaptic plasticity in male rat and the activity‐dependent recruitment of androgenic and estrogenic pathways leading to LTD and LTP, respectively.

Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.

Subjective visual vertical before and after treatment of a BPPV episode

OBJECTIVE The study analyses the behavior of subjective visual vertical (SVV) in benign paroxysmal positional vertigo (BPPV) before and after treatment, and offers a clinical-pathogenic interpretation. METHODS We studied 30 consecutive patients with BPPV of the posterior semicircular canal treated with the Epley repositioning maneuver. SVV was determined at three different stages: at the time of diagnosis (1st test), after the repositioning maneuver (2nd test), and then 7 days after the resolution of the clinical picture (3rd test). The main study parameter was represented by the mean of 6 consecutive measurements (SVV(0)) for each patient. SVV was also examined in 20 healthy subjects, who represented the control group. The comparison between mean values and standard deviations showed a statistical significance of p<0.05. RESULTS During the first test, the degree of deviation of SVV was significantly higher in the patient group than in the control group. Tilting towards the affected side was observed in all cases. The 2nd test showed an inversion in the orientation of SVV in 16 patients, and as a result of the Epley maneuver there was a statistically significant variation in SVV(0) values in 20 patients with respect to the previous test (2nd test vs. 1st test). This involved 87% (23 patients) of those who then had a negative Dix-Hallpike test, and none of the ones in whom paroxysmal positional nystagmus persisted. Lastly, no differences emerged in the behavior of the patient group vs. the control group during the third test. CONCLUSIONS SVV is often altered during active BPPV. The degree of otolithic dysfunction is never high and, in all cases, it is brief in duration. Tilting towards the dysfunctional side is essentially a constant in untreated BPPV. This could be due to a substantial loss of otoconia, with a decrease in the density and specific weight of the macula, and thus hypofunction of the receptor. The observation of a significant variation in SVV after therapeutic maneuvers has a favorable predictive value, as it probably reflects the migration of otoliths to the utricle, where saturation mechanisms can often have irritative effects leading to the inversion of SVV.

The repetition timing of high frequency afferent stimulation drives the bidirectional plasticity at central synapses in the rat medial vestibular nuclei.

In this study we show that high frequency stimulation (HFS, 100Hz) of afferent fibers to the medial vestibular nucleus (MVN) can induce opposite long-term modifications of synaptic responses in the type B neurons depending upon the stimulation pattern. Long burst stimulation (LBS: 2s) and short burst stimulation (SBS: 0.55s) were applied with different burst number (BN) and inter-burst intervals (IBI). It results that both LBS and SBS can induce either N-methyl-d aspartate receptors (NMDARs)-mediated long-term potentiation (LTP) or long-term depression (LTD), depending on temporal organization of repetitive bursts. In particular, the IBI plays a relevant role in guiding the shift from LTP to LTD since by using both LBS and SBS LTP is induced by shorter IBI than LTD. By contrast, the sign of long-term effect does not depend on the mean impulse frequency evaluated within the entire stimulation period. Therefore, the patterns of repetitive vestibular activation with different ratios between periods of increased activity and periods of basal activity may lead to LTP or LTD probably causing different levels of postsynaptic Ca(2+). On the whole, this study demonstrates that glutamatergic vestibular synapse in the MVN can undergo NMDAR-dependent bidirectional plasticity and puts forward a new aspect for understanding the adaptive and compensatory plasticity of the oculomotor responses.

Long-lasting effects of neck muscle vibration and contraction on self-motion perception of vestibular origin

OBJECTIVE To show that neck proprioceptive input can induce long-term effects on vestibular-dependent self-motion perception. METHODS Motion perception was assessed by measuring the subjects error in tracking in the dark the remembered position of a fixed target during whole-body yaw asymmetric rotation of a supporting platform, consisting in a fast rightward half-cycle and a slow leftward half-cycle returning the subject to the initial position. Neck muscles were relaxed or voluntarily contracted, and/or vibrated. Whole-body rotation was administered during or at various intervals after the vibration train. The tracking position error (TPE) at the end of the platform rotation was measured during and after the muscle conditioning maneuvers. RESULTS Neck input produced immediate and sustained changes in the vestibular perceptual response to whole-body rotation. Vibration of the left sterno-cleido-mastoideus (SCM) or right splenius capitis (SC) or isometric neck muscle effort to rotate the head to the right enhanced the TPE by decreasing the perception of the slow rotation. The reverse effect was observed by activating the contralateral muscle. The effects persisted after the end of SCM conditioning, and slowly vanished within several hours, as tested by late asymmetric rotations. The aftereffect increased in amplitude and persistence by extending the duration of the vibration train (from 1 to 10min), augmenting the vibration frequency (from 5 to 100Hz) or contracting the vibrated muscle. Symmetric yaw rotation elicited a negligible TPE, upon which neck muscle vibrations were ineffective. CONCLUSIONS Neck proprioceptive input induces enduring changes in vestibular-dependent self-motion perception, conditional on the vestibular stimulus feature, and on the side and the characteristics of vibration and status of vibrated muscles. This shows that our perception of whole-body yaw-rotation is not only dependent on accurate vestibular information, but is modulated by proprioceptive information related to previously experienced position of head with respect to trunk. SIGNIFICANCE Tonic proprioceptive inflow, as might occur as a consequence of enduring or permanent head postures, can induce adaptive plastic changes in vestibular-dependent motion sensitiveness. These changes might be counteracted by vibration of selected neck muscles.

Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.