Tiziana Florio - Academia.edu (original) (raw)

Papers by Tiziana Florio

Research paper thumbnail of Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model

Oncotarget, Jan 19, 2015

Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting ther... more Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in...

Research paper thumbnail of Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling

Oncotarget, Jan 26, 2015

In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor init... more In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, ...

Research paper thumbnail of The pedunculopontine nucleus and related structures. Functional organization

Research paper thumbnail of High-frequency stimulation of the subthalamic nucleus modulates the activity of pedunculopontine neurons through direct activation of excitatory fibres as well as through indirect activation of inhibitory pallidal fibres in the rat

European Journal of Neuroscience

Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in ... more Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinson's disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN-high-frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single-shock stimulations in the three experimental groups was a short latency (4.5 +/- 2.1 ms) and brief (15.3 +/- 6.5 ms) excitation. This response was maintained during 1-5 s of STN-HFS (130 Hz, 60 micros, 100-1000 microA). In EP-lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN-HFS was significantly higher compared with that observed in intact (39.7%) and in SN-lesioned rats (35.4%). Furthermore, in EP-lesioned rats the most frequent response of PP...

Research paper thumbnail of The pedunculopontine nucleus projection to the parafascicular nucleus of the thalamus: an electrophysiological investigation in the rat

Journal of neural transmission (Vienna, Austria : 1996), 2003

Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the tha... more Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the thalamus were done in normal rats and in rats bearing lesions of either the cerebellar nuclei or the entopeduncular nucleus to investigate the functional control of the pedunculopontine nucleus on the parafascicular nucleus. A total of 97 neurons were recorded in the parafascicular nucleus in intact rats, 83 in rats bearing a chronic electrolytic lesion of the ipsilateral deep cerebellar nuclei, and 69 in rats bearing an ibotenate lesion of the ipsilateral entopeduncular nucleus. Lesions of the cerebellar nuclei or the entopeduncular nucleus were made to evaluate the participation of cerebellothalamic fibers or of polysynaptic basal ganglia circuits in the responses recorded in parafascicular neurons following electrical microstimulation of the ipsilateral pedunculopontine nucleus. Two types of excitation and one type of inhibition were the main responses observed in neurons of the parafasc...

Research paper thumbnail of Regulatory Action of the Dopaminergic Nigrostriatal Pathway on the Corticostriatal Transmission

Advances in Behavioral Biology, 1994

Research paper thumbnail of PPARβ/δ and γ in a Rat Model of Parkinson's Disease: Possible Involvement in PD Symptoms

Journal of cellular biochemistry, Jan 19, 2014

Parkinson's disease is one of the most common neurologic disorder, affecting about 1-4% of pe... more Parkinson's disease is one of the most common neurologic disorder, affecting about 1-4% of persons older than 60 years. Among the proposed mechanisms of PD generation, free radical damage is believed to play a pivotal role in the development and/or progression of the disease. Recently, PPARs, a class of transcription factors involved in several pathways both in physiological and pathological conditions, have been linked by us and others to neurodegeneration. Particularly, PPARγ and its ligands have been indicated as potential therapeutic targets for the treatment of several pathological conditions associated with neuroinflammation within the CNS. The anti-inflammatory function of PPARγ has attracted attention since agonists exert a broad spectrum of protective effects in several animal models of neurological diseases, including psychiatric diseases. On the other hand a detrimental role for PPARβ/δ has been proposed in Alzheimer, being closely related to the decrease of BDNF and ...

Research paper thumbnail of The pedunculopontine tegmental nucleus: implications for a role in modulating spinal cord motoneuron excitability

Journal of Neural Transmission, 2011

There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PP... more There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PPTg) improves parkinsonian motor signs. The mechanisms that mediate these effects and the modifications that occur in the PPTg in Parkinson's disease (PD) are not fully known and are the object of current debate. The aim of this paper was to critically review available data with respect to (1) the presence of PPTg neurons linked to reticulospinal projections, (2) the involvement of these neurons in modulating spinal reflexes, and (3) the participation of fibers close to or within the PPTg region in such modulation. The PPTg neurons are distributed in a large pontotegmental region, stimulation of which can evoke activity in hindlimb, shoulder and neck muscles, and potentiate motor responses evoked by stimulation of dorsal roots. This influence seems to be carried out by fast-conducting descending fibers, which likely run in the medial reticulospinal pathway. It is yet unclear which neurotransmitters are involved and on which elements of the gray matter of the spinal cord PPTg fibers synapse. The modulation of spinal cord activity which can be achieved by stimulating the PPTg region seems to be mediated not only by PPTg neurons, but also by tecto-reticular fibers which run in the pontotegmental area, and which likely are activated during PPTg-DBS. The importance of these fibers is discussed taking into account the degeneration of PPTg neurons in PD and the benefits in gait and postural control that PPTg-DBS exerts in PD. The potential usefulness of PPTg-DBS in other neurodegenerative disorders characterized by neuronal loss in the brainstem is also considered.

Research paper thumbnail of Low frequency stimulation of the pedunculopontine nucleus modulates electrical activity of subthalamic neurons in the rat

Journal of Neural Transmission, 2009

Electrical stimulation of the rat pedunculopontine nucleus (PPTg) (<25 Hz)... more Electrical stimulation of the rat pedunculopontine nucleus (PPTg) (<25 Hz) synchronized firing of subthalamic neurons (STN) with each stimulus, and a continuous irregular activity often preceded recovery of burst discharges in control as well as in 6-hydroxydopamine lesioned animals. Firing was blocked both by increasing frequency of stimulation (>50 Hz) and current intensity (>500 microA). The data suggest that clinically relevant frequencies for PPTg deep brain stimulation in Parkinson's disease modulate burst discharges in STN neurons.

Research paper thumbnail of Polymorphism of DQA1 promoter in Italian population

Research paper thumbnail of Transplantation of Mesencephalic Cell Suspension in Dopamine-Denervated Striatum of the Rat

Experimental Neurology, 1997

These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic n... more These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic neurons induce recovery of normal discharge patterns in striatal neurons of rats after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) pathway. Lesioned rats were tested for rotational behavior induced by amphetamine and apomorphine. Animals which responded positively to these tests received two suspensions of mesencephalic embryonic neurons into the dorsal striatum (ST) ipsilateral to the denervated side. Sham-grafted rats received the suspension medium only. The vitality of the graft was assessed by the disappearance or reversion of rotational movements induced by amphetamine. Extracellular recordings of neurons located throughout the ST were carried out 3 months after grafting, when the animals reached the age of 6 months. The 6-OHDAinduced nigral lesion caused a net increase both in the number of striatal neurons spontaneously active and in their discharging rates. The signs of increased neuronal activity were also present in sham-grafted animals. The grafting of embryonal cells strongly reduced the number of active neurons and decreased significantly their discharging rate. The effects of the intrastriatal graft appeared to be present within a radius of 1.5-2 mm from the core of the grafted area. The presence of tyrosine-hydroxylase-immunopositive neurons innervating the host ST confirmed the viability of the grafts at the time of electrophysiological recording. The results show that besides compensating motor asymmetries caused by DA denervation, intrastriatally grafted dopaminergic neurons are able to only partially restore the electrophysiological action of DA in discrete striatal domains. r

Research paper thumbnail of High frequency stimulation of the subthalamic nucleus modulates neurotransmission in limbic brain regions of the rat

Experimental Brain Research, 2008

Research paper thumbnail of Evidence that non-NMDA receptors are involved in the excitatory pathway from the pedunculopontine region to nigrostriatal dopaminergic neurons

Experimental Brain Research, 1992

Extracellular single-neuron recordings were obtained from electrophysiologically identified nigro... more Extracellular single-neuron recordings were obtained from electrophysiologically identified nigrostriatal neurons in chloral hydrate anesthetized rats, in order to test the hypothesis that excitatory amino acid receptors are involved in responses of these neurons to electrical stimulation of the pontine region where the pedunculopontine nucleus (PPN) is located. The effects of iontophoretic application of excitatory amino acids and their antagonists as well as of cholinergic antagonists were tested on the fast orthodromic excitation of nigrostriatal neurons evoked by stimulation of the PPN region. The N-methyl-D-aspartate (NMDA) receptor antagonist D-a-aminoadipic acid as well as the cholinergic receptor antagonists mecamylamine and atropine failed to suppress the synaptic excitation of nigral neurons. The NMDA receptor antagonist DL-2-amino-5phosphonovalerate exerted a weak depressant action on the synaptic response in a few neurons only. On the contrary, the broad spectrum antagonists of excitatory amino acid receptors kynurenic acid and gamma-Dglutamyl-amino-methyl-sulphonate were found to block simultaneously both the synaptic excitation and the neuronal responses to iontophoretic pulses of glutamate while leaving unaffected the neuronal responses to local application of acetylcholine or carbachol. The competitive antagonist of non-NMDA receptors 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline suppressed the synaptic excitation at ejection currents which antagonized neuronal responses to quisqualate and kainate. These results suggest that PPN excitatory fibers synapsing onto pars compacta nigrostriatal neurons utilize an excitatory amino acid as a synaptic transmitter acting preferentially on non-NMDA receptors.

Research paper thumbnail of Behavioural learning-induced increase in spontaneous GABAA-dependent synaptic activity in rat striatal cholinergic interneurons

European Journal of Neuroscience, 2003

Cholinergic striatal interneurons play a crucial role in cognitive aspects of context-dependent m... more Cholinergic striatal interneurons play a crucial role in cognitive aspects of context-dependent motor behaviours. They are considered to correspond to the tonically active neurons (TANs) of the primate striatum, which phasically decrease their discharge at the presentation of reward-related sensory stimuli. The origin of this response is still poorly understood. Therefore, in the present paper, we have investigated whether synaptic changes establish in cholinergic interneurons from young rats that have learned a rewarded, externally cued sensorimotor task. Corticostriatal slices were prepared from both control and trained rats. No significant change in intrinsic membrane properties and evoked synaptic activity was observed in cholinergic interneurons, nor the responsiveness to exogenously applied dopaminergic and glutamatergic agonists was modified. Conversely, an increased occurrence of spontaneous bicucullinesensitive depolarizing postsynaptic potentials (sDPSP) was recorded. The frequency of the GABA A -mediated sDPSP was increased in comparison to not-conditioned rats. Overall, these results suggest that after learning a rewarded sensorimotor paradigm an increased GABA influence develops on cholinergic interneurons. The origin of this effect might be searched in collaterals of GABAergic output spiny neurons as well as in GABAergic striatal interneurons impinging onto cholinergic interneurons. This intrastriatal mechanism might be involved in the phasic suppression of discharge of TANs at the presentation of reward-related sensory stimuli.

Research paper thumbnail of Unilateral deep brain stimulation of the pedunculopontine tegmental nucleus improves oromotor movements in Parkinson’s disease

Brain Stimulation, 2012

Jaw movements are severely affected in Parkinson's diseas... more Jaw movements are severely affected in Parkinson's disease. Deep brain stimulation (DBS) of basal ganglia targets is known to ameliorate oromotor control. In this study, we examined the effects of DBS of the pedunculopontine tegmental nucleus (PPTg) on jaw movements in selected parkinsonian patients. The effects of low-frequency (25 Hz) stimulation of the PPTg on jaw movements were investigated through electrognathographic analysis in parkinsonian patients who were selected for PPTg stimulation. Changes in jaw velocity and amplitude during voluntary opening and closing movements of the mouth, as well as the maximum frequency of self-paced sequences of opening and closing cycles, were analyzed. Low-frequency stimulation of the PPTg in the OFF-drugs condition significantly improved the opening and closing velocities, vertical amplitude and rhythm of voluntary movements. In some instances, movement parameters during stimulation were within the range of those recorded in healthy controls. This is the first study investigating the impact of PPTg DBS on oromotor control in parkinsonian patients. The results show that jaw movements may be restored under stimulation and suggest that the pedunculopontine nucleus may play a key role in controlling oromotor activity.

Research paper thumbnail of Influence of prelimbic and sensorimotor cortices on striatal neurons in the rat: electrophysiological evidence for converging inputs and the effects of 6-OHDA-induced degeneration of the substantia nigra

Research paper thumbnail of Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat

Behavioural Brain Research, 2001

Lesions of the subthalamic nucleus (STN) in the rat are known to cause anticipated movements in b... more Lesions of the subthalamic nucleus (STN) in the rat are known to cause anticipated movements in behavioral tasks requiring a preparatory period before the execution of externally cued conditioned movements. In the present study, we describe the effects of lesions of the pedunculopontine nucleus (PPN), a structure located on the outflow of the STN to lower brainstem and spinal motor nuclei, on the anticipatory responding caused by a unilateral lesion of the STN in a delayed sensorimotor task. Rats were instructed to keep a lever pressed down by the presentation of a composite visual and acoustic signal, and were required to hold the lever pressed until a trigger stimulus occurred after an unpredictable delay. The trigger stimulus required the animals to release the lever and to press a second lever for food reinforcement. The task was evaluated according to analysis of movement parameters and errors made by the animals during the preparative and executive phases of the conditioned movement. An ibotenate lesion was placed into the STN in either side of the brain. This lesion was followed 3 weeks later by an ibotenate lesion of the PPN ipsilaterally to the STN previously lesioned. The results indicate that the anticipatory responding induced by the STN lesion was not alleviated by the subsequent PPN lesion. However, the animals bearing the combined lesion were severely impaired in conditioned responding to salient stimuli involved in the paradigm and showed side-specific lengthening of reaction and movement times without global motor impairments. The results suggest that the anticipatory responses caused by STN lesions do not require the intervention of the PPN and that the disruption of the dopaminergic nigrostriatal pathway following the combined lesion may be responsible for impairments observed.

Research paper thumbnail of The function of the pedunculopontine nucleus in the preparation and execution of an externally-cued bar pressing task in the rat

Behavioural Brain Research, 1999

In the present study the role of the pedunculopontine nucleus (PPN) in the preparation and execut... more In the present study the role of the pedunculopontine nucleus (PPN) in the preparation and execution of an externally-cued rewarded motor act was investigated. Animals were instructed to press down a lever at the presentation of a combined visual and acoustic signal and were required to hold down the lever until a trigger stimulus occurred after an unpredictable delay ranging from 2 to 4 s. The trigger stimulus required animals to release the lever and to press a second lever for food reinforcement. The time between instruction and trigger signals represented the preparation phase preceding movement. Unilateral ibotenic acid-induced focal degeneration of pedunculopontine neurons did not influence either reaction and movement times, or capacity of the animals to correctly respond to presentation of stimuli of behavioral significance. On the contrary, bilateral lesions increased both reaction and movement times, and dramatically reduced the percentage of correct responses. The analysis of incorrect responses suggested that the most striking deficit exhibited by the animals following the bilateral lesion was a lack of conditioned response to the signal initiating each trial. However, the animals retained the capability to respond correctly in some trials, and were able to collect the reward when delivered outside the behavioral context. Histological analysis of lesions showed that in addition to loss of neurons within the pedunculopontine region, reduction of tyrosine-hydroxylase positive neurons had occurred in the pars compacta of the substantia nigra. The data suggest that the PPN is involved in the preparation and execution of externally-cued movements, and demonstrate that its destruction mimics the main effects produced by the dopaminergic denervation of the dorsal striatum.

Research paper thumbnail of Dopamine denervation of specific striatal subregions differentially affects preparation and execution of a delayed response task in the rat

Behavioural Brain Research, 1999

In the present study, the effects of unilateral or bilateral dopamine denervation of either the d... more In the present study, the effects of unilateral or bilateral dopamine denervation of either the dorsal or ventral striatum on the preparation and execution of a delayed response task in the rat were investigated. Animals were instructed to hold a lever pressed down by the presentation of a visual and/or acoustic signal, and were required to hold the lever until a trigger stimulus occurred after an unpredictable delay ranging from 2 to 4 s. The trigger stimulus required animals to release the lever and to press a second lever for food reinforcement. The time between instruction and trigger signal represented the preparation phase preceding movement. The motor performance was evaluated by using reaction and movement times in addition to correct responses in each session. Dopaminergic denervation of either the dorsal or ventral striatum ipsilaterally to the side in which the second lever to be pressed was located did not significantly change reaction and movement times, although it reduced the percentage of correct trials. A significant increase of both reaction and movement times was recorded only after bilateral denervation of the ventral striatum. The analysis of incorrect responses indicated that dopaminergic innervation of the two striatal subregions had different functions in the correct execution of the behavioral paradigm. In the group of animals with dorsal lesions the most frequent incorrect response was represented by a lack of the conditioned response to the presentation of the instruction stimulus starting the trial. If the animals reacted properly to this signal, the performance thereafter was correct in the majority of trials. Conversely, animals with ventral lesions exhibited a large repertoire of incorrect responses throughout the paradigm, including premature release or delayed press of levers, and omission of the second lever press. Histological verification of brain coronal sections by tyrosine-hydroxylase immunoreactivity showed that the lesions were confined in either the dorsal or ventral striatum, sparing the lateral region. The data support the hypothesis that dopaminergic innervation enables the two striatal regions to differently participate in the preparation and execution of complex delayed sensorimotor tasks. Indeed, the dorsal striatum seems to be involved in the correct utilization of external sensory information for the initiation of conditioned behavior, whereas, the ventral striatum appears to be mainly concerned with the temporal expectation of impending stimuli that trigger reward-reinforced movements.

Research paper thumbnail of Switching ability of over trained movements in a Parkinson’s disease rat model

Behavioural Brain Research, 2013

Patients with Parkinson&a... more Patients with Parkinson's disease show unbalanced capability to manage self-paced vs externally driven movements, or automatic-associated movements with respect to the intended voluntary movements. We studied the effect of a selective loss of dopaminergic terminals within the striatum and the execution of a well-learned set-shifting task as revealed using tyrosine hydroxylase immunoreactivity and magnetic resonance imaging in the rat. We found that, both in the externally cued condition, and in the externally-internally driven switching task, the cue-dependent constraints interfered with motor readiness in over training condition. The unilateral dopaminergic striatal depletion enhanced the switch-induced performance differences in favour of the internally-externally cued transition. Dopamine depleted rats, in fact, were impaired to produce an alternative motion when task switching required to change from an over trained behaviour, towards an alternative self-paced response. The comparative analysis of behavioural, tyrosine hydroxylase immunoreactivity and magnetic resonance imaging data, revealed a shrinkage of the lesioned striatum, and an enlargement of the ipsilateral ventricle that could provide useful markers for monitoring pathological changes occurring during early stages of Parkinson's disease in vivo.

Research paper thumbnail of Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model

Oncotarget, Jan 19, 2015

Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting ther... more Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in...

Research paper thumbnail of Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling

Oncotarget, Jan 26, 2015

In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor init... more In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, ...

Research paper thumbnail of The pedunculopontine nucleus and related structures. Functional organization

Research paper thumbnail of High-frequency stimulation of the subthalamic nucleus modulates the activity of pedunculopontine neurons through direct activation of excitatory fibres as well as through indirect activation of inhibitory pallidal fibres in the rat

European Journal of Neuroscience

Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in ... more Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinson's disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN-high-frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single-shock stimulations in the three experimental groups was a short latency (4.5 +/- 2.1 ms) and brief (15.3 +/- 6.5 ms) excitation. This response was maintained during 1-5 s of STN-HFS (130 Hz, 60 micros, 100-1000 microA). In EP-lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN-HFS was significantly higher compared with that observed in intact (39.7%) and in SN-lesioned rats (35.4%). Furthermore, in EP-lesioned rats the most frequent response of PP...

Research paper thumbnail of The pedunculopontine nucleus projection to the parafascicular nucleus of the thalamus: an electrophysiological investigation in the rat

Journal of neural transmission (Vienna, Austria : 1996), 2003

Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the tha... more Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the thalamus were done in normal rats and in rats bearing lesions of either the cerebellar nuclei or the entopeduncular nucleus to investigate the functional control of the pedunculopontine nucleus on the parafascicular nucleus. A total of 97 neurons were recorded in the parafascicular nucleus in intact rats, 83 in rats bearing a chronic electrolytic lesion of the ipsilateral deep cerebellar nuclei, and 69 in rats bearing an ibotenate lesion of the ipsilateral entopeduncular nucleus. Lesions of the cerebellar nuclei or the entopeduncular nucleus were made to evaluate the participation of cerebellothalamic fibers or of polysynaptic basal ganglia circuits in the responses recorded in parafascicular neurons following electrical microstimulation of the ipsilateral pedunculopontine nucleus. Two types of excitation and one type of inhibition were the main responses observed in neurons of the parafasc...

Research paper thumbnail of Regulatory Action of the Dopaminergic Nigrostriatal Pathway on the Corticostriatal Transmission

Advances in Behavioral Biology, 1994

Research paper thumbnail of PPARβ/δ and γ in a Rat Model of Parkinson's Disease: Possible Involvement in PD Symptoms

Journal of cellular biochemistry, Jan 19, 2014

Parkinson's disease is one of the most common neurologic disorder, affecting about 1-4% of pe... more Parkinson's disease is one of the most common neurologic disorder, affecting about 1-4% of persons older than 60 years. Among the proposed mechanisms of PD generation, free radical damage is believed to play a pivotal role in the development and/or progression of the disease. Recently, PPARs, a class of transcription factors involved in several pathways both in physiological and pathological conditions, have been linked by us and others to neurodegeneration. Particularly, PPARγ and its ligands have been indicated as potential therapeutic targets for the treatment of several pathological conditions associated with neuroinflammation within the CNS. The anti-inflammatory function of PPARγ has attracted attention since agonists exert a broad spectrum of protective effects in several animal models of neurological diseases, including psychiatric diseases. On the other hand a detrimental role for PPARβ/δ has been proposed in Alzheimer, being closely related to the decrease of BDNF and ...

Research paper thumbnail of The pedunculopontine tegmental nucleus: implications for a role in modulating spinal cord motoneuron excitability

Journal of Neural Transmission, 2011

There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PP... more There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PPTg) improves parkinsonian motor signs. The mechanisms that mediate these effects and the modifications that occur in the PPTg in Parkinson's disease (PD) are not fully known and are the object of current debate. The aim of this paper was to critically review available data with respect to (1) the presence of PPTg neurons linked to reticulospinal projections, (2) the involvement of these neurons in modulating spinal reflexes, and (3) the participation of fibers close to or within the PPTg region in such modulation. The PPTg neurons are distributed in a large pontotegmental region, stimulation of which can evoke activity in hindlimb, shoulder and neck muscles, and potentiate motor responses evoked by stimulation of dorsal roots. This influence seems to be carried out by fast-conducting descending fibers, which likely run in the medial reticulospinal pathway. It is yet unclear which neurotransmitters are involved and on which elements of the gray matter of the spinal cord PPTg fibers synapse. The modulation of spinal cord activity which can be achieved by stimulating the PPTg region seems to be mediated not only by PPTg neurons, but also by tecto-reticular fibers which run in the pontotegmental area, and which likely are activated during PPTg-DBS. The importance of these fibers is discussed taking into account the degeneration of PPTg neurons in PD and the benefits in gait and postural control that PPTg-DBS exerts in PD. The potential usefulness of PPTg-DBS in other neurodegenerative disorders characterized by neuronal loss in the brainstem is also considered.

Research paper thumbnail of Low frequency stimulation of the pedunculopontine nucleus modulates electrical activity of subthalamic neurons in the rat

Journal of Neural Transmission, 2009

Electrical stimulation of the rat pedunculopontine nucleus (PPTg) (<25 Hz)... more Electrical stimulation of the rat pedunculopontine nucleus (PPTg) (<25 Hz) synchronized firing of subthalamic neurons (STN) with each stimulus, and a continuous irregular activity often preceded recovery of burst discharges in control as well as in 6-hydroxydopamine lesioned animals. Firing was blocked both by increasing frequency of stimulation (>50 Hz) and current intensity (>500 microA). The data suggest that clinically relevant frequencies for PPTg deep brain stimulation in Parkinson's disease modulate burst discharges in STN neurons.

Research paper thumbnail of Polymorphism of DQA1 promoter in Italian population

Research paper thumbnail of Transplantation of Mesencephalic Cell Suspension in Dopamine-Denervated Striatum of the Rat

Experimental Neurology, 1997

These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic n... more These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic neurons induce recovery of normal discharge patterns in striatal neurons of rats after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) pathway. Lesioned rats were tested for rotational behavior induced by amphetamine and apomorphine. Animals which responded positively to these tests received two suspensions of mesencephalic embryonic neurons into the dorsal striatum (ST) ipsilateral to the denervated side. Sham-grafted rats received the suspension medium only. The vitality of the graft was assessed by the disappearance or reversion of rotational movements induced by amphetamine. Extracellular recordings of neurons located throughout the ST were carried out 3 months after grafting, when the animals reached the age of 6 months. The 6-OHDAinduced nigral lesion caused a net increase both in the number of striatal neurons spontaneously active and in their discharging rates. The signs of increased neuronal activity were also present in sham-grafted animals. The grafting of embryonal cells strongly reduced the number of active neurons and decreased significantly their discharging rate. The effects of the intrastriatal graft appeared to be present within a radius of 1.5-2 mm from the core of the grafted area. The presence of tyrosine-hydroxylase-immunopositive neurons innervating the host ST confirmed the viability of the grafts at the time of electrophysiological recording. The results show that besides compensating motor asymmetries caused by DA denervation, intrastriatally grafted dopaminergic neurons are able to only partially restore the electrophysiological action of DA in discrete striatal domains. r

Research paper thumbnail of High frequency stimulation of the subthalamic nucleus modulates neurotransmission in limbic brain regions of the rat

Experimental Brain Research, 2008

Research paper thumbnail of Evidence that non-NMDA receptors are involved in the excitatory pathway from the pedunculopontine region to nigrostriatal dopaminergic neurons

Experimental Brain Research, 1992

Extracellular single-neuron recordings were obtained from electrophysiologically identified nigro... more Extracellular single-neuron recordings were obtained from electrophysiologically identified nigrostriatal neurons in chloral hydrate anesthetized rats, in order to test the hypothesis that excitatory amino acid receptors are involved in responses of these neurons to electrical stimulation of the pontine region where the pedunculopontine nucleus (PPN) is located. The effects of iontophoretic application of excitatory amino acids and their antagonists as well as of cholinergic antagonists were tested on the fast orthodromic excitation of nigrostriatal neurons evoked by stimulation of the PPN region. The N-methyl-D-aspartate (NMDA) receptor antagonist D-a-aminoadipic acid as well as the cholinergic receptor antagonists mecamylamine and atropine failed to suppress the synaptic excitation of nigral neurons. The NMDA receptor antagonist DL-2-amino-5phosphonovalerate exerted a weak depressant action on the synaptic response in a few neurons only. On the contrary, the broad spectrum antagonists of excitatory amino acid receptors kynurenic acid and gamma-Dglutamyl-amino-methyl-sulphonate were found to block simultaneously both the synaptic excitation and the neuronal responses to iontophoretic pulses of glutamate while leaving unaffected the neuronal responses to local application of acetylcholine or carbachol. The competitive antagonist of non-NMDA receptors 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline suppressed the synaptic excitation at ejection currents which antagonized neuronal responses to quisqualate and kainate. These results suggest that PPN excitatory fibers synapsing onto pars compacta nigrostriatal neurons utilize an excitatory amino acid as a synaptic transmitter acting preferentially on non-NMDA receptors.

Research paper thumbnail of Behavioural learning-induced increase in spontaneous GABAA-dependent synaptic activity in rat striatal cholinergic interneurons

European Journal of Neuroscience, 2003

Cholinergic striatal interneurons play a crucial role in cognitive aspects of context-dependent m... more Cholinergic striatal interneurons play a crucial role in cognitive aspects of context-dependent motor behaviours. They are considered to correspond to the tonically active neurons (TANs) of the primate striatum, which phasically decrease their discharge at the presentation of reward-related sensory stimuli. The origin of this response is still poorly understood. Therefore, in the present paper, we have investigated whether synaptic changes establish in cholinergic interneurons from young rats that have learned a rewarded, externally cued sensorimotor task. Corticostriatal slices were prepared from both control and trained rats. No significant change in intrinsic membrane properties and evoked synaptic activity was observed in cholinergic interneurons, nor the responsiveness to exogenously applied dopaminergic and glutamatergic agonists was modified. Conversely, an increased occurrence of spontaneous bicucullinesensitive depolarizing postsynaptic potentials (sDPSP) was recorded. The frequency of the GABA A -mediated sDPSP was increased in comparison to not-conditioned rats. Overall, these results suggest that after learning a rewarded sensorimotor paradigm an increased GABA influence develops on cholinergic interneurons. The origin of this effect might be searched in collaterals of GABAergic output spiny neurons as well as in GABAergic striatal interneurons impinging onto cholinergic interneurons. This intrastriatal mechanism might be involved in the phasic suppression of discharge of TANs at the presentation of reward-related sensory stimuli.

Research paper thumbnail of Unilateral deep brain stimulation of the pedunculopontine tegmental nucleus improves oromotor movements in Parkinson’s disease

Brain Stimulation, 2012

Jaw movements are severely affected in Parkinson's diseas... more Jaw movements are severely affected in Parkinson's disease. Deep brain stimulation (DBS) of basal ganglia targets is known to ameliorate oromotor control. In this study, we examined the effects of DBS of the pedunculopontine tegmental nucleus (PPTg) on jaw movements in selected parkinsonian patients. The effects of low-frequency (25 Hz) stimulation of the PPTg on jaw movements were investigated through electrognathographic analysis in parkinsonian patients who were selected for PPTg stimulation. Changes in jaw velocity and amplitude during voluntary opening and closing movements of the mouth, as well as the maximum frequency of self-paced sequences of opening and closing cycles, were analyzed. Low-frequency stimulation of the PPTg in the OFF-drugs condition significantly improved the opening and closing velocities, vertical amplitude and rhythm of voluntary movements. In some instances, movement parameters during stimulation were within the range of those recorded in healthy controls. This is the first study investigating the impact of PPTg DBS on oromotor control in parkinsonian patients. The results show that jaw movements may be restored under stimulation and suggest that the pedunculopontine nucleus may play a key role in controlling oromotor activity.

Research paper thumbnail of Influence of prelimbic and sensorimotor cortices on striatal neurons in the rat: electrophysiological evidence for converging inputs and the effects of 6-OHDA-induced degeneration of the substantia nigra

Research paper thumbnail of Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat

Behavioural Brain Research, 2001

Lesions of the subthalamic nucleus (STN) in the rat are known to cause anticipated movements in b... more Lesions of the subthalamic nucleus (STN) in the rat are known to cause anticipated movements in behavioral tasks requiring a preparatory period before the execution of externally cued conditioned movements. In the present study, we describe the effects of lesions of the pedunculopontine nucleus (PPN), a structure located on the outflow of the STN to lower brainstem and spinal motor nuclei, on the anticipatory responding caused by a unilateral lesion of the STN in a delayed sensorimotor task. Rats were instructed to keep a lever pressed down by the presentation of a composite visual and acoustic signal, and were required to hold the lever pressed until a trigger stimulus occurred after an unpredictable delay. The trigger stimulus required the animals to release the lever and to press a second lever for food reinforcement. The task was evaluated according to analysis of movement parameters and errors made by the animals during the preparative and executive phases of the conditioned movement. An ibotenate lesion was placed into the STN in either side of the brain. This lesion was followed 3 weeks later by an ibotenate lesion of the PPN ipsilaterally to the STN previously lesioned. The results indicate that the anticipatory responding induced by the STN lesion was not alleviated by the subsequent PPN lesion. However, the animals bearing the combined lesion were severely impaired in conditioned responding to salient stimuli involved in the paradigm and showed side-specific lengthening of reaction and movement times without global motor impairments. The results suggest that the anticipatory responses caused by STN lesions do not require the intervention of the PPN and that the disruption of the dopaminergic nigrostriatal pathway following the combined lesion may be responsible for impairments observed.

Research paper thumbnail of The function of the pedunculopontine nucleus in the preparation and execution of an externally-cued bar pressing task in the rat

Behavioural Brain Research, 1999

In the present study the role of the pedunculopontine nucleus (PPN) in the preparation and execut... more In the present study the role of the pedunculopontine nucleus (PPN) in the preparation and execution of an externally-cued rewarded motor act was investigated. Animals were instructed to press down a lever at the presentation of a combined visual and acoustic signal and were required to hold down the lever until a trigger stimulus occurred after an unpredictable delay ranging from 2 to 4 s. The trigger stimulus required animals to release the lever and to press a second lever for food reinforcement. The time between instruction and trigger signals represented the preparation phase preceding movement. Unilateral ibotenic acid-induced focal degeneration of pedunculopontine neurons did not influence either reaction and movement times, or capacity of the animals to correctly respond to presentation of stimuli of behavioral significance. On the contrary, bilateral lesions increased both reaction and movement times, and dramatically reduced the percentage of correct responses. The analysis of incorrect responses suggested that the most striking deficit exhibited by the animals following the bilateral lesion was a lack of conditioned response to the signal initiating each trial. However, the animals retained the capability to respond correctly in some trials, and were able to collect the reward when delivered outside the behavioral context. Histological analysis of lesions showed that in addition to loss of neurons within the pedunculopontine region, reduction of tyrosine-hydroxylase positive neurons had occurred in the pars compacta of the substantia nigra. The data suggest that the PPN is involved in the preparation and execution of externally-cued movements, and demonstrate that its destruction mimics the main effects produced by the dopaminergic denervation of the dorsal striatum.

Research paper thumbnail of Dopamine denervation of specific striatal subregions differentially affects preparation and execution of a delayed response task in the rat

Behavioural Brain Research, 1999

In the present study, the effects of unilateral or bilateral dopamine denervation of either the d... more In the present study, the effects of unilateral or bilateral dopamine denervation of either the dorsal or ventral striatum on the preparation and execution of a delayed response task in the rat were investigated. Animals were instructed to hold a lever pressed down by the presentation of a visual and/or acoustic signal, and were required to hold the lever until a trigger stimulus occurred after an unpredictable delay ranging from 2 to 4 s. The trigger stimulus required animals to release the lever and to press a second lever for food reinforcement. The time between instruction and trigger signal represented the preparation phase preceding movement. The motor performance was evaluated by using reaction and movement times in addition to correct responses in each session. Dopaminergic denervation of either the dorsal or ventral striatum ipsilaterally to the side in which the second lever to be pressed was located did not significantly change reaction and movement times, although it reduced the percentage of correct trials. A significant increase of both reaction and movement times was recorded only after bilateral denervation of the ventral striatum. The analysis of incorrect responses indicated that dopaminergic innervation of the two striatal subregions had different functions in the correct execution of the behavioral paradigm. In the group of animals with dorsal lesions the most frequent incorrect response was represented by a lack of the conditioned response to the presentation of the instruction stimulus starting the trial. If the animals reacted properly to this signal, the performance thereafter was correct in the majority of trials. Conversely, animals with ventral lesions exhibited a large repertoire of incorrect responses throughout the paradigm, including premature release or delayed press of levers, and omission of the second lever press. Histological verification of brain coronal sections by tyrosine-hydroxylase immunoreactivity showed that the lesions were confined in either the dorsal or ventral striatum, sparing the lateral region. The data support the hypothesis that dopaminergic innervation enables the two striatal regions to differently participate in the preparation and execution of complex delayed sensorimotor tasks. Indeed, the dorsal striatum seems to be involved in the correct utilization of external sensory information for the initiation of conditioned behavior, whereas, the ventral striatum appears to be mainly concerned with the temporal expectation of impending stimuli that trigger reward-reinforced movements.

Research paper thumbnail of Switching ability of over trained movements in a Parkinson’s disease rat model

Behavioural Brain Research, 2013

Patients with Parkinson&a... more Patients with Parkinson's disease show unbalanced capability to manage self-paced vs externally driven movements, or automatic-associated movements with respect to the intended voluntary movements. We studied the effect of a selective loss of dopaminergic terminals within the striatum and the execution of a well-learned set-shifting task as revealed using tyrosine hydroxylase immunoreactivity and magnetic resonance imaging in the rat. We found that, both in the externally cued condition, and in the externally-internally driven switching task, the cue-dependent constraints interfered with motor readiness in over training condition. The unilateral dopaminergic striatal depletion enhanced the switch-induced performance differences in favour of the internally-externally cued transition. Dopamine depleted rats, in fact, were impaired to produce an alternative motion when task switching required to change from an over trained behaviour, towards an alternative self-paced response. The comparative analysis of behavioural, tyrosine hydroxylase immunoreactivity and magnetic resonance imaging data, revealed a shrinkage of the lesioned striatum, and an enlargement of the ipsilateral ventricle that could provide useful markers for monitoring pathological changes occurring during early stages of Parkinson's disease in vivo.