René Garcia

Inertial, Substratal and Landmark Cue Control of Hippocampal CA1 Place Cell Activity

Hippocampal ‘place cells’ discharge when a rat occupies a location that is fixed in relation to environmental landmarks. A principal goal of this study was to determine whether hippocampal place cell activity could be influenced by inertial cues. Water‐deprived rats were trained in a square‐walled open field in a dark room. The behavioural task required alternating visits to water reservoirs in the centre and in the four corners of the arena. The rat and arena were rotated in total darkness through ±90, 180 or 270°. The next water reward was then presented in the corner at the same position relative to the outside room as before the rotation. A cue card was later illuminated in this corner as a visual cue for the extra‐arena (room) reference frame. Fifteen out of 97 recorded hippocampal CA1 complex spike cells had spatially selective discharges in non‐central parts of the arena. After arena rotations, the firing fields of three units shifted between corners of the arena to maintain a fixed orientation relative to the room. This indicates that the hippocampus updated its representation of the position and heading direction of the rat using vestibular‐derived inputs concerning rotation angle. Other spatially selective discharges were guided to landmark cues (cue card or position of the reward: two units) or arena‐locked ‘substratal’ cues (eight units). In six cells, place cell activity suddenly ceased or appeared following rotations. These results provide evidence for contributions of inertial as well as substratal and landmark information to hippocampal spatial representations.

Time-dependent blockade of STP and LTP in hippocampal slices following acute stress in mice

The characteristics of short-term potentiation (STP) and long-term potentiation (LTP) in the CA1 region of hippocampal slices were determined at various times following exposure to acute stress produced by restraint and tail-shock in mice. In slices prepared from control animals, theta-burst stimulation resulted in a large increase in evoked field excitatory postsynaptic potentials (EPSPs) amplitude and slope that remained stable at least up to 30 min after stimulation. Slices prepared 1 h after stress exhibited a marked decrease in the extent of both STP and LTP. STP and LTP magnitude were still significantly decreased 24 h after stress exposure and were completely restored to control levels by 48 h. These results provide evidence for a reversible impairment of STP and LTP in CA1 following an acute episode of stress, and suggest that stress activates processes different from those activated by LTP-inducing stimuli.

Potentiation of conditioned freezing following dorsomedial prefrontal cortex lesions does not interfere with fear reduction in mice

In Experiment 1, an auditory conditioned stimulus (CS) was paired with footshock, except when it was preceded by another stimulus (a visual conditioned inhibitor [CI]). After conditioning, all mice displayed less CS-evoked freezing when the CI-CS compound was presented than when the CS was presented alone. However, lesions of the dorsomedial prefrontal cortex (dmPFC) potentiated CS-evoked freezing on each of the 2 sessions (i.e., CI CS and CS alone). In Experiment 2, mice were submitted to fear extinction (CS-alone presentation for 3 days). Lesioned mice exhibited a higher level of freezing behavior than controls on each of the 3 sessions. However, lesioned mice and controls displayed the same rate of reduction of freezing over the 3 days of extinction. These data in mice support previous studies in rats, which suggests that the dmPFC is not critical for either conditioned inhibition or extinction of acquired freezing behavior.

Changes in Synaptic Excitability in the Lateral Septum Associated with Contextual and Auditory Fear Conditioning in Mice

Synaptic excitability in the lateral septum (LS) was assessed electrophysiologically in freely moving mice either submitted to a painful stimulus (shock) or tested on two forms of conditioned fear: contextual conditioning and auditory cue conditioning. Only the amplitude of the N3 component of the two negative waves (N2 and N3) evoked by fimbrial stimulation displayed significant changes in these tests. Experiment 1 showed that both the painful stimulus and subsequent re‐exposure (24 h later) to the conditioning foreground context induced significant and context specific decrease in the N3 amplitude. In Experiment 2, a phasic tone (conditioned stimulus: CS) was paired (paired group) with the footshock (unconditioned stimulus: US) or not (unpaired group) and, 24 h later, animals were re‐exposed successively to the auditory cue and to the context. During the auditory cue test, only the paired group displayed significant freezing and this occurred only during presentation of the CS. In this group, however, a significant reduction in the N3 amplitude was only observed immediately after the cessation of the CS. During the context test, the percentage and time‐course of freezing across the 10 min session were similar in each group. However, in the unpaired group the N3 amplitude reduction was significant and outlasted the duration of the freezing behaviour itself. These results show that alterations in LS synaptic excitability may be dissociated from fear‐induced freezing behaviour. We suggest that LS synapses are part of a brain circuit that predict if and when the US is going to occur.

Opposite effects of lateral septal LTP and lateral septal lesions on contextual fear conditioning in mice.

The effect of fimbrial high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the lateral septum (LS) on contextual fear conditioning was studied in mice. Mice were conditioned for fear toward a novel context through the use of footshocks. The 1st experiment showed that pretraining HFS reduced significantly conditional freezing to contextual stimuli. The 2nd experiment was designed to determine whether the reduction of freezing produced by fimbrial HFS resulted from LTP in the LS rather than from LTP in other brain structures. Accordingly, mice with lesions of the LS were used and submitted to the same protocol as in the 1st experiment. Results showed that LS lesions completely abolished the impairing effect of fimbrial HFS and, as a whole, potentiated the freezing response. These data suggest that contextual fear conditioning is strongly modulated by the level of hippocampal-LS synaptic neurotransmission.

Exposure to a conditioned aversive environment interferes with long-term potentiation induction in the fimbria-CA3 pathway

The effect of re-exposure of rats to an aversive environment on the induction of long-term potentiation was investigated in the CA3 region 3 and 12 h after contextual conditioning. Electro-physiological recordings showed that re-exposure of rats to the conditioning chamber produced a significant and long-lasting decrease in population spike amplitude at both post-conditioning delays. High-frequency stimulation of the fimbria induced a large and persistent increase in CA3 population spike amplitude (about 400% of baseline) in animals of control groups and shocked animals that were not re-exposed to the conditioning environment. However, high-frequency stimulation applied during re-exposure of shocked subjects 3 h after the initial exposure resulted in a small and transient increase in population spike amplitude (about 140% of baseline); when applied 12 h after the initial exposure, it produced a persistent depression of the response (-30% of baseline). Behavioural testing indicated that re-exposure of shocked animals to the conditioning environment elicited a qualitatively and quantitatively similar freezing behaviour at both post-conditioning delays (3 or 12 h). In contrast to the long-lasting decrease in CA3 population spike amplitude produced by re-exposure to the aversive environment, the level of freezing behaviour diminished rapidly within 10 min of exposure. These results suggest that, during exposure to a conditioned aversive environment, alterations in fimbria-CA3 neural processing may be dissociated from contextual fear-induced freezing behaviour. In addition, processes underlying long-term potentiation induction in fimbria-CA3 pathway may be opposite to those taking place during hippocampal processing of conditioned aversive contexts.

Footshock stress but not contextual fear conditioning induces long-term enhancement of auditory-evoked potentials in the basolateral amygdala of the freely behaving rat.

In this study, rats were bilaterally implanted with electrodes in the amygdala for chronic recording. Auditory click stimulation evoked in the basolateral nucleus a field potential characterized by three positive components: P1, P2 and P3 (peak latencies around: 10, 20 and 30 ms, respectively) which were each followed by three negative components: N1, N2 and N3 (peak latencies around: 13, 30 and 50 ms, respectively). Animals were divided into three groups (context‐same, context‐different and control). Following footshock administration, animals were either re‐exposed to the same conditioning chamber (context‐same group) or placed in a different context (context‐different group) for electrophysiological and behavioural (evaluation of freezing response) recordings. The two early positive‐negative complexes (P1‐N1 and P2‐N2) increased in amplitude from 2 min to 24 h following footshock in both context‐same and context‐different groups. No significant difference was observed between these two groups. The demonstration of significantly larger freezing responses in context‐same subjects on exposure to the aversive conditioned environment indicated that this similarity of effects was not due to lack of conditioning of context under the experimental conditions chosen. We conclude that footshock stress produces general long‐lasting changes in amygdala auditory field potentials that are not significantly affected by contextual fear conditioning.

Long-term potentiation and long-term depression in the lateral septum in spatial working and reference memory

We report two experiments conducted on a radial arm maze in the mouse showing that training could either enhance or reduce the efficacy of the fimbria-lateral septal synapses. It is suggested that the direction of change is determined by the kind of situation the animal is faced with (ie trial-dependent, respectively).

Pretraining tetanic fimbrial stimulation impairs the expression but not the acquisition of contextual fear conditioning in mice.

We recently reported that the pretraining induction of long-term potentiation in the lateral septum by fimbrial tetanic stimulation altered contextual fear conditioning in mice. The aim of the present study was to examine at which stage of fear conditioning (i.e. either acquisition or expression) this impairment takes place. Mice implanted with stimulating electrodes in the fimbria and recording electrodes in the lateral septal were conditioned to acquire fear towards a novel context using a footshock procedure. Twenty-four hours after conditioning, animals were re-exposed to the conditioning environment and the level of freezing behavior served as the measure of conditioned fear. The level of fimbrial-lateral septal synaptic neurotransmission was manipulated using either fimbrial tetanic stimulation (which induced septal long-term potentiation) alone, or followed by fimbrial low-frequency stimulation producing depotentiation of the previously established long-term potentiation. The results showed that (i) septal long-term potentiation induced either prior to acquisition or only prior to retention testing impaired conditioned freezing; and (ii) the impairing effect of pretraining induction of long-term potentiation on conditioned freezing was not only abolished by fimbrial low-frequency stimulation administered prior to retention testing but actually produced enhanced conditioned freezing with respect to controls. These data suggest that the level of fimbrial-lateral septal synaptic neurotransmission may influence the expression, but not the acquisition, of contextual fear conditioning.

Influences of the bed nucleus of the stria terminalis and of the paraventricular nucleus of the hypothalamus on the excitability of hippocampal-lateral septal synapses in mice

Previous experiments have shown that conditioning in aversive situations is associated with specific changes in excitability of hippocampal-septal synaptic transmission and that these changes might be related to a modulation of this synaptic transmission by afferents originating from the bed nucleus of the stria terminalis (BNST) and from the paraventricular nucleus (PVN) of the hypothalamus. Accordingly, the aim of the present experiment was to assess changes in excitability of hippocampal-septal synapses by varying the interval between the application of a conditioning pulse in either the BNST or the PVN, and a test pulse in fimbria fibers (FF). Electrical stimulation of FF, induces in the lateral septum (LS) a field potential characterized by two negative waves (N2 and N3) the magnitude of which is an index of excitability of two populations of target cells located in the ventral and dorsal lateral septum, respectively. Results showed that prestimulation of both the BNST and the PVN produced an increase in the amplitude of the N3 wave, although the optimal interpulse interval required for producing maximal increase was different as a function of the two structures. Only prestimulation of the BNST induced a significant increase in the amplitude of the N2 wave. These results suggest that the PVN projects mainly to the dorsal aspect of the LS, while the BNST projects to both dorsal and ventral parts of the LS. Together with results from previous experiments conducted in behaving mice exposed to conditioned aversive stimuli, it is concluded that these projections might play a role in the relief of contextual conditioned fear.