| 1. |
- Lorenzon, Paolo, et al.
(författare)
-
Estrus-specific synaptic inhibition of accessory olfactory bulb output neurons in response to vagino-cervical stimulation
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This is the first study of the electrophysiological response of accessory olfactory bulb (AOB) output neurons to vagino-cervical stimulation by in vivo whole-cell recordings, allowing for measurements at synaptic input and spike output level in identified microcircuit cell types in naturally cycling mice. AOB is relaying specialized odorous information and e.g. shows plasticity essential for formation of a vomeronasal organ (VNO)-pheromonal memory of the mating male. Thus, not only VNO-pheromonal information, but also representation of coital somatosensory information needs to reach AOB. AOB in vivo responses to VNO-pheromones does not correlate in time to stimulus. We find that vagino-cervical stimuli evoke a stimulus-locked response in AOB regardless if the female is in estrus or not, and the response is sensitive to noradrenergic α1-adrenergic receptor blockade. By retrograde labeling we confirm that norepinephrine-producing locus coeruleus neurons innervate the AOB and functional anatomy demonstrated that vagino-cervical information reaches locus coeruleus in both estrus and diestrus. The spontaneous activity of mitral-tufted output neurons show propensity to fire bursts of spikes specifically during estrus suggesting state-dependent excitability of the network. Intriguingly, only during estrus do the output neurons show norepinephrine-dependent, dendro-dendritic inhibition of spike output during vagino-cervical stimulation, which is accompanied by longer activation of inhibitory granule cell layer of AOB. Thus, the estrous state of the circuit appears required for coital stimulation to evoke synaptic inhibition in main output neurons of the microcircuit, which may contribute to formation of memory of the mating male, possibly via burst-dependent increase of dendro-dendritic inhibition
|
|
| 2. |
- Lorenzon, Paolo, et al.
(författare)
-
In vivo spontaneous activity and coital-evoked inhibition of mouse accessory olfactory bulb output neurons
- 2023
-
Ingår i: iScience. - : Elsevier. - 2589-0042. ; 26:9
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about estrous effects on brain microcircuits. We examined the accessory olfactory bulb (AOB) in vivo, in anesthetized naturally cycling females, as model microcircuit receiving coital somatosensory information. Whole-cell recordings demonstrate that output neurons are relatively hyperpolarized in estrus and unexpectedly fire high frequency bursts of action potentials. To mimic coitus, a calibrated artificial vagino-cervical stimulation (aVCS) protocol was devised. aVCS evoked stimulus-locked local field responses in the interneuron layer independent of estrous stage. The response is sensitive to α1-adrenergic receptor blockade, as expected since aVCS increases norepinephrine release in AOB. Intriguingly, only in estrus does aVCS inhibit AOB spike output. Estrus-specific output reduction coincides with prolonged aVCS activation of inhibitory interneurons. Accordingly, in estrus the AOB microcircuit sets the stage for coital stimulation to inhibit the output neurons, possibly via high frequency bursting-dependent enhancement of reciprocal synapse efficacy between inter- and output neurons.
|
|
| 3. |
- Tran, Phong, et al.
(författare)
-
De novo dNTP production is essential for normal postnatal murine heart development
- 2019
-
Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 394:44, s. 15889-15897
-
Tidskriftsartikel (refereegranskat)abstract
- The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in wild-type postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in wildtype hearts.
|
|
| 4. |
- Bartoletti, Alessandro, et al.
(författare)
-
Environmental enrichment prevents effects of dark-rearing in the rat visual cortex
- 2004
-
Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 7:3, s. 215-216
-
Tidskriftsartikel (refereegranskat)abstract
- Environmental enrichment potentiates neural plasticity, enhancing acquisition and consolidation of memory traces. In the sensory cortices, after cortical circuit maturation and sensory function acquisition are completed, neural plasticity declines and the critical period 'closes'. In the visual cortex, this process can be prevented by dark-rearing, and here we show that environmental enrichment can promote physiological maturation and consolidation of visual cortical connections in dark-reared rats, leading to critical period closure.
|
|
| 5. |
- Blau, Axel, et al.
(författare)
-
Flexible, all-polymer microelectrode arrays for the capture of cardiac and neuronal signals
- 2011
-
Ingår i: Biomaterials. - : Elsevier. - 0142-9612 .- 1878-5905. ; 32:7, s. 1778-1786
-
Tidskriftsartikel (refereegranskat)abstract
- Microelectrode electrophysiology has become a widespread technique for the extracellular recording of bioelectrical signals. To date, electrodes are made of metals or inorganic semiconductors, or hybrids thereof. We demonstrate that these traditional conductors can be completely substituted by highly flexible electroconductive polymers. Pursuing a two-level replica-forming strategy, conductive areas for electrodes, leads and contact pads are defined as microchannels in poly(dimethylsiloxane) (PDMS) as a plastic carrier and track insulation material. These channels are coated by films of organic conductors such as polystyrenesulfonate-doped poly(3,4-ethylenedioxy-thiophene) (PEDOT:PSS) or filled with a graphite-PDMS (gPDMS) composite, either alone or in combination. The bendable, somewhat stretchable, non-cytotoxic and biostable all-polymer microelectrode arrays (polyMEAs) with a thickness below 500 μm and up to 60 electrodes reliably capture action potentials (APs) and local field potentials (LFPs) from acute preparations of heart muscle cells and retinal whole mounts, in vivo epicortical and epidural recordings as well as during long-term in vitro recordings from cortico-hippocampal co-cultures.
|
|
| 6. |
- Caleo, Matteo, et al.
(författare)
-
Provision of brain-derived neurotrophic factor via anterograde transport from the eye preserves the physiological responses of axotomized geniculate neurons.
- 2003
-
Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 23:1, s. 287-96
-
Tidskriftsartikel (refereegranskat)abstract
- The neurotrophic factors of the nerve growth factor family (neurotrophins) have been shown to promote neuronal survival after brain injury and in various models of neurodegenerative conditions. However, it has not been determined whether neurotrophin treatment results in the maintenance of function of the rescued cells. Here we have used the retrograde degeneration of geniculate neurons as a model system to evaluate neuronal rescue and sparing of function after administration of brain-derived neurotrophic factor (BDNF). Death of geniculate neurons was induced by a visual cortex lesion in adult rats, and exogenous BDNF was delivered to the axotomized geniculate cells via anterograde transport after injection into the eye. By microelectrode recordings from the geniculate in vivo we have measured several physiological parameters such as contrast threshold, spatial resolution (visual acuity), signal-to-noise ratio, temporal resolution, and response latency. In control lesioned animals we found that geniculate cell dysfunction precedes the onset of neuronal death, indicating that an assessment of neuronal number per se is not predictive of functional performance. The administration of BDNF resulted in a highly significant cell-saving effect up to 2 weeks after the cortical damage and maintained nearly normal physiological responses in the geniculate. This preservation of function in adult axotomized neurons suggests possible therapeutic applications of BDNF.
|
|
| 7. |
- Iurilli, Giuliano, et al.
(författare)
-
Loss of Visually Driven Synaptic Responses in Layer 4 Regular-Spiking Neurons of Rat Visual Cortex in Absence of Competing Inputs
- 2012
-
Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 22:9, s. 2171-2181
-
Tidskriftsartikel (refereegranskat)abstract
- Monocular deprivation (MD) during development shifts the ocular preference of primary visual cortex (V1) neurons by depressing closed-eye responses and potentiating open-eye responses. As these 2 processes are temporally and mechanistically distinct, we tested whether loss of responsiveness occurs also in absence of competing inputs. We thus compared the effects of long-term MD in layer 4 regular-spiking pyramidal neurons (L4Ns) of binocular and monocular V1 (bV1 and mV1) with whole-cell recordings. In bV1, input depression was larger than potentiation, and the ocular dominance shift was larger for spike outputs. MD-but not retinal inactivation with tetrodotoxin-caused a comparable loss of synaptic and spike responsiveness in mV1, which is innervated only by the deprived eye. Conversely, brief MD depressed synaptic responses only in bV1. MD-driven depression in mV1 was accompanied by a proportional reduction of visual thalamic inputs, as assessed upon pharmacological silencing of intracortical transmission. Finally, sub- and suprathreshold responsiveness was similarly degraded in L4Ns of bV1 upon complete deprivation of patterned vision through a binocular deprivation period of comparable length. Thus, loss of synaptic inputs from the deprived eye occurs also in absence of competition in the main thalamorecipient lamina, albeit at a slower pace.
|
|
| 8. |
- Iurilli, Giuliano, et al.
(författare)
-
Preserved Excitatory-Inhibitory Balance of Cortical Synaptic Inputs following Deprived Eye Stimulation after a Saturating Period of Monocular Deprivation in Rats
- 2013
-
Ingår i: PloS one. - : PLOS ONE. - 1932-6203. ; 8:12, s. e82044-
-
Tidskriftsartikel (refereegranskat)abstract
- Monocular deprivation (MD) during development leads to a dramatic loss of responsiveness through the deprived eye in primary visual cortical neurons, and to degraded spatial vision (amblyopia) in all species tested so far, including rodents. Such loss of responsiveness is accompanied since the beginning by a decreased excitatory drive from the thalamo-cortical inputs. However, in the thalamorecipient layer 4, inhibitory interneurons are initially unaffected by MD and their synapses onto pyramidal cells potentiate. It remains controversial whether ocular dominance plasticity similarly or differentially affects the excitatory and inhibitory synaptic conductances driven by visual stimulation of the deprived eye and impinging onto visual cortical pyramids, after a saturating period of MD. To address this issue, we isolated visually-driven excitatory and inhibitory conductances by in vivo whole-cell recordings from layer 4 regular-spiking neurons in the primary visual cortex (V1) of juvenile rats. We found that a saturating period of MD comparably reduced visually-driven excitatory and inhibitory conductances driven by visual stimulation of the deprived eye. Also, the excitatory and inhibitory conductances underlying the synaptic responses driven by the ipsilateral, left open eye were similarly potentiated compared to controls. Multiunit recordings in layer 4 followed by spike sorting indicated that the suprathreshold loss of responsiveness and the MD-driven ocular preference shifts were similar for narrow spiking, putative inhibitory neurons and broad spiking, putative excitatory neurons. Thus, by the time the plastic response has reached a plateau, inhibitory circuits adjust to preserve the normal balance between excitation and inhibition in the cortical network of the main thalamorecipient layer.
|
|
| 9. |
- Iurilli, Giuliano, et al.
(författare)
-
Sound-Driven Synaptic Inhibition in Primary Visual Cortex
- 2012
-
Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 73:4, s. 814-28
-
Tidskriftsartikel (refereegranskat)abstract
- Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.
|
|
| 10. |
- Jamroskovic, Jan, et al.
(författare)
-
Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
- 2020
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:6, s. 2876-2888
-
Tidskriftsartikel (refereegranskat)abstract
- The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.
|
|
