Modulation of cortical slow oscillatory rhythm by GABAB receptors: an in vitro experimental and computational study.

KEY POINTS: We confirm that GABAB receptors (GABAB -Rs) are involved in the termination of Up-states; their blockade consistently elongates Up-states. GABAB -Rs also modulate Down-states and the oscillatory cycle, thus having an impact on slow oscillation rhythm and its regularity. The most frequent effect of GABAB -R blockade is elongation of Down-states and subsequent decrease of oscillatory frequency, with an increased regularity. In a quarter of cases, GABAB -R blockade shortened Down-states and increased oscillatory frequency, changes that are independent of firing rates in Up-states. Our computer model provides mechanisms for the experimentally observed dynamics following blockade of GABAB -Rs, for Up/Down durations, oscillatory frequency and regularity. The time course of excitation, inhibition and adaptation can explain the observed dynamics of the network. This study brings novel insights into the role of GABAB -R-mediated slow inhibition on the slow oscillatory activity, which is considered the default activity pattern of the cortical network. ABSTRACT: Slow wave oscillations (SWOs) dominate cortical activity during deep sleep, anaesthesia and in some brain lesions. SWOs are composed of periods of activity (Up states) interspersed with periods of silence (Down states). The rhythmicity expressed during SWOs integrates neuronal and connectivity properties of the network and is often altered under pathological conditions. Adaptation mechanisms as well as synaptic inhibition mediated by GABAB receptors (GABAB -Rs) have been proposed as mechanisms governing the termination of Up states. The interplay between these two mechanisms is not well understood, and the role of GABAB -Rs controlling the whole cycle of the SWO has not been described. Here we contribute to its understanding by combining in vitro experiments on spontaneously active cortical slices and computational techniques. GABAB -R blockade modified the whole SWO cycle, not only elongating Up states, but also affecting the subsequent Down state duration. Furthermore, while adaptation tends to yield a rather regular behaviour, we demonstrate that GABAB -R activation desynchronizes the SWOs. Interestingly, variability changes could be accomplished in two different ways: by either shortening or lengthening the duration of Down states. Even when the most common observation following GABAB -Rs blocking is the lengthening of Down states, both changes are expressed experimentally and also in numerical simulations. Our simulations suggest that the sluggishness of GABAB -Rs to follow the excitatory fluctuations of the cortical network can explain these different network dynamics modulated by GABAB -Rs.

Inhibitory modulation of cortical up states.

The balance between excitation and inhibition is critical in the physiology of the cerebral cortex. To understand the influence of inhibitory control on the emergent activity of the cortical network, inhibition was progressively blocked in a slice preparation that generates spontaneous rhythmic up states at a similar frequency to those occurring in vivo during slow-wave sleep or anesthesia. Progressive removal of inhibition induced a parametric shortening of up state duration and elongation of the down states, the frequency of oscillations decaying. Concurrently, a gradual increase in the network firing rate during up states occurred. The slope of transitions between up and down states was quantified for different levels of inhibition. The slope of upward transitions reflects the recruitment of the local network and was progressively increased when inhibition was decreased, whereas the speed of activity propagation became faster. Removal of inhibition eventually resulted in epileptiform activity. Whereas gradual reduction of inhibition induced linear changes in up/down states and their propagation, epileptiform activity was the result of a nonlinear transformation. A computational network model showed that strong recurrence plus activity-dependent hyperpolarizing currents were sufficient to account for the observed up state modulations and predicted an increase in activity-dependent hyperpolarization following up states when inhibition was decreased, which was confirmed experimentally.

Hyperpolarization-activated graded persistent activity in the prefrontal cortex.

We describe a phenomenon of hyperpolarization-activated graded persistent activity (HAGPA) in prefrontal cortex neurons. Successive hyperpolarizing pulses induced increasingly higher rates of tonic firing that remained stable for tens of seconds, allowing the neuron to retain a memory of the previous history of stimulation. This phenomenon occurred at the cellular level and in the absence of neuromodulators. Neurons with HAGPA had a sag during hyperpolarization, and blocking h-current eliminated the sag and prevented HAGPA, suggesting that the activation of this hyperpolarization-activated cationic current was necessary for the occurrence of the phenomenon. A single-neuron biophysical model including h-current modulation by intracellular calcium was able to display HAGPA. This form of neuronal memory not only allows the transformation of inhibition into an increase of firing rate, but also endows neurons with a mechanism to compute the properties of successive inputs into persistent activity, thus solving a difficult computational problem.

Early activation of extracellular signal-regulated kinase signaling pathway in the hippocampus is required for short-term memory formation of a fear-motivated learning.

1. According to its duration there are, at least, two major forms of memory in mammals: short term memory (STM) which develops in a few seconds and lasts several hours and long-term memory (LTM) lasting days, weeks and even a lifetime. In contrast to LTM, very little is known about the neural, cellular and molecular requirements for mammalian STM formation. 2. Here we show that early activation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus is required for the establishment of STM for a one-trial inhibitory avoidance task in the rat. Immediate posttraining infusion of U0126 (a selective inhibitor of ERK kinase) into the CA1 region of the dorsal hippocampus blocked STM formation. 3. Reversible inactivation of the entorhinal cortex through muscimol infusion produced deficits in STM and a selective and rapid decrease in hippocampal ERK2 activation.4. Together with our previous findings showing a rapid decrease in ERK2 activation and impaired STM after blocking BDNF function, the present results strongly suggest that ERK2 signaling in the hippocampus is a critical step in STM processing.

Detection of novelty, but not memory of spatial habituation, is associated with an increase in phosphorylated cAMP response element-binding protein levels in the hippocampus.

There is a growing body of evidence showing that the formation of associative memories is associated with an increase in phosphorylated cAMP response element-binding protein (pCREB) levels. We recently reported increased pCREB levels in the rat hippocampus after an exploration to a novel environment. In the present work, we studied whether this increment in CREB activation is associated with the formation of memory of habituation to a novel environment or with the detection of novelty. Rats were submitted to consecutive open field sessions at 3-h intervals. Measurement of the hippocampal pCREB level, carried out 1 h after each training session, showed that (1) it did not increase when rats explored a familiar environment; (2) it did not increase after a reexposure that improves the memory of habituation; (3) it increased after a brief novel exploration unable to form memory of habituation; and (4) it increased in amnesic rats for spatial habituation. Taken as a whole, our results suggest that the elevated pCREB level after a single open field exploration is not associated with the memory formation of habituation. It is indeed associated with the detection of a novel environment.