Development of osteoporosis severely complicates long-term glucocorticoid (GC) therapy. Using a Cre-transgenic mouse line, we now demonstrate that GCs are unable to repress bone formation in the absence of glucocorticoid receptor (GR) expression in osteoblasts as they become refractory to hormone-induced apoptosis, inhibition of proliferation, and differentiation. In contrast, GC treatment still reduces bone formation in mice carrying a mutation that only disrupts GR dimerization, resulting in bone loss in vivo, enhanced apoptosis, and suppressed differentiation in vitro. The inhibitory GC effects on osteoblasts can be explained by a mechanism involving suppression of cytokines, such as interleukin 11, via interaction of the monomeric GR with AP-1, but not NF-kappaB. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy.

. Neocortical pyramidal cells respond as integrate-and-fire neurons to in vivo-like input currents. J Neurophysiol 90: 1598 -1612, 2003. First published May 15, 2003 10.1152/jn.00293.2003. In the intact brain neurons are constantly exposed to intense synaptic activity. This heavy barrage of excitatory and inhibitory inputs was recreated in vitro by injecting a noisy current, generated as an Ornstein-Uhlenbeck process, into the soma of rat neocortical pyramidal cells. The response to such in vivo-like currents was studied systematically by analyzing the time development of the instantaneous spike frequency, and when possible, the stationary mean spike frequency as a function of both the mean and the variance of the input current. All cells responded with an in vivo-like action potential activity with stationary statistics that could be sustained throughout long stimulation intervals (tens of seconds), provided the frequencies were not too high. The temporal evolution of the response revealed the presence of mechanisms of fast and slow spike frequency adaptation, and a medium duration mechanism of facilitation. For strong input currents, the slow adaptation mechanism made the spike frequency response nonstationary. The minimal frequencies that caused strong slow adaptation (a decrease in the spike rate by more than 1 Hz/s), were in the range 30 -80 Hz and depended on the pipette solution used. The stationary response function has been fitted by two simple models of integrate-and-fire neurons endowed with a frequency-dependent modification of the input current. This accounts for all the fast and slow mechanisms of adaptation and facilitation that determine the stationary response, and proved necessary to fit the model to the experimental data. The coefficient of variability of the interspike interval was also in part captured by the model neurons, by tuning the parameters of the model to match the mean spike frequencies only. We conclude that the integrate-and-fire model with spike-frequency-dependent adaptation/facilitation is an adequate model reduction of cortical cells when the mean spikefrequency response to in vivo-like currents with stationary statistics is considered. I N T R O D U C T I O NSingle neuron properties have been thoroughly investigated in the past years showing that neural cells are rich in phenomenology and complex in their structure (see, e.g., Mainen and Sejnowski 1996;McCormick et al. 1985;Rhodes 1999). Even the most detailed state-of-the-art model is unable to capture the entire phenomenology observed in the experiments. Such a richness calls for a model reduction that could provide a synthetic description of the response properties of the cells under particular conditions. We studied in vitro those features that are supposedly relevant when the cell is embedded in a large network of interconnected neurons, as it would be in in vivo conditions. The guidelines for selecting the relevant features were dictated by the theoretical framework developed in the last decade to study the dynamic pr...

Recurrence 1Electrical stimulation (ES) is used in animals and humans to study potential causal links between neural activity and specific cognitive functions. Recently, it has found increased application in electrotherapy and neural prostheses as well. However, how ES-elicited signals propagate in brain tissues is still unclear. Here we used combined electrostimulation, neurophysiology, microinjection and fMRI to study the cortical activity patterns elicited during stimulation of cortical afferents in monkeys. We find that stimulation of a site in LGN (lateral geniculate nucleus) increases the fMRI signal in the regions of primary visual cortex (V1) receiving input from that site, but suppresses it in the retinotopically matched regions of extrastriate cortex. In agreement with previous observations, intracranial recordings show that immediately after a stimulation pulse a long-lasting inhibition follows a short excitatory response. Following microinjections of GABA (γ-aminobutyric acid) antagonists in V1, LGN stimulation induces positive fMRI signals in all cortical areas. Taken together, our findings suggest that ES disrupts cortico-cortical signal propagation by silencing the output of any neocortical area whose afferents are electrically stimulated.We recently developed and optimized the esfMRI (combined ES and fMRI) methodology for experiments in anesthetized and behaving monkeys 1, 2 . Our first experiments, including fMRI-based estimations of tissue excitability (rheobase and chronaxie measurements), showed that electrical stimulation of the primary visual cortex V1 mainly excites large pyramidal cells and axons, eliciting positive BOLD responses (PBR) in topographically matched regions of extrastriate areas such as V2, V3, V3A, V4, and MT (V5); all monosynaptic targets of the primary visual cortex. These findings are consistent with the well-established anatomical connections between V1 and the extrastriate cortex of macaque monkeys 3 . One puzzling observation in our initial studies was the clear lack of transsynaptic effects during cortical stimulation. In the present study, we stimulated either the LGN or the pulvinar (Pul) in anesthetized and alert monkeys in order to systematically examine the propagation of ES-induced signals.We demonstrate that electrical stimulation of a thalamic site indeed suppresses the neural activity of its projection regions in visual cortex. The strong reduction in BOLD response is likely due to synaptic inhibition and it be can be reversed by injections of GABA antagonists in V1. In agreement with the fMRI results, intracortical recordings show that an electric pulse evokes an action potential followed by a pronounced and long-lasting inhibition. Such disruptive effects of cortical afferent stimulation on the activity of projection neurons have already been reported. Yet, by using the combined physiology, pharmacology and fMRI approach here we illustrate for the first time the extent and generality of ES-induced activity suppression, and we propose that many behavioral e...

Neurons generate spikes reliably with millisecond precision if driven by a fluctuating current-is it then possible to predict the spike timing knowing the input? We determined parameters of an adapting threshold model using data recorded in vitro from 24 layer 5 pyramidal neurons from rat somatosensory cortex, stimulated intracellularly by a fluctuating current simulating synaptic bombardment in vivo. The model generates output spikes whenever the membrane voltage (a filtered version of the input current) reaches a dynamic threshold. We find that for input currents with large fluctuation amplitude, up to 75% of the spike times can be predicted with a precision of ± 2 ms. Some of the intrinsic neuronal unreliability can be accounted for by a noisy threshold mechanism. Our results suggest that, under random current injection into the soma, (i) neuronal behavior in the subthreshold regime can be well approximated by a simple linear filter; and (ii) most of the nonlinearities are captured by a simple threshold process.