Changes in ensemble activity of hippocampus CA1 neurons induced by chronic morphine administration in freely behaving mice

The hippocampus plays an important role in the formation of new memories and spatial navigation. Recently, growing evidence supports the view that it is also involved in addiction to opiates and other drugs. Theoretical and experimental studies suggest that hippocampal neural-network oscillations at specific frequencies and unit firing patterns reflect information of learning and memory encoding. Here, using multichannel recordings from the hippocampal CA1 area in behaving mice, we investigated the phase correlations between the theta (4-10 Hz) and gamma (40-100 Hz) oscillations, and the timing of spikes modulated by these oscillations. Local field potentials and single unit recordings in the CA1 area of mice receiving chronic morphine treatment revealed that the power of the theta rhythm was strongly increased; at the same time, the theta frequency during different behavioral states shifted markedly, and the characteristic coupling of theta and gamma oscillations was altered. Surprisingly, though the gamma oscillation frequency changed, the power of gamma lacking theta did not. Moreover, the timing of pyramidal cell spikes relative to the theta rhythm and the timing of interneuron spikes relative to the gamma rhythm changed during chronic morphine administration. Furthermore, these responses were impaired by a selective D1/D5 receptor antagonist intra-hippocampus injection. These results indicate that chronic morphine administration induced the changes of ensemble activity in the CA1 area, and these changes were dependent on local dopamine receptor activation.     

Spike phase precession persists after transient intrahippocampal perturbation

Oscillatory spike timing in the hippocampus is regarded as a temporal coding mechanism for space, but the underlying mechanisms are poorly understood. To contrast the predictions of the different models of phase precession, we transiently turned off neuronal discharges for up to 250 ms and reset the phase of theta oscillations by stimulating the commissural pathway in rats. After recovery from silence, phase precession continued. The phase of spikes for the first theta cycle after the perturbation was more advanced than the phase of spikes for the last theta cycle just before the perturbation. These findings indicate that phase advancement that emerges within hippocampal circuitry may be updated at the beginning of each theta cycle by extrahippocampal inputs.     

Septo-hippocampal networks in chronically epileptic rats: potential antiepileptic effects of theta rhythm generation

A series of experiments was carried out testing the hypothesis that the septal region decreases the hippocampal susceptibility to hyperexcitability states through theta rhythm generation. Medial septal neurons were simultaneously recorded with hippocampal field potentials to investigate the septo-hippocampal function in the pilocarpine model of chronic epilepsy. The theta rhythm from chronically epileptic rats had lower amplitude (20% less) and higher frequency than controls (from 3.38 to 4.25 Hz), suggesting that both generator and pacemaker structures are affected during the epileptic process. At the cellular level, the group of rhythmically bursting firing medial septal neurons, in the epileptic animals, significantly and chronically increased their firing rates in relation to controls (from 13.86 to 29.14 spikes/s). Peristimulus histograms performed around hippocampal sharp waves showed that all high-frequency firing neurons, including rhythmically bursting neurons and most slow firing neurons, decreased firing rates immediately after hippocampal epileptic discharges. Thus inhibitory hippocampo-septal influences prevail during hippocampal epileptic discharges. The occurrence of epileptic discharges was reduced 86-97% of the number observed during spontaneous theta and theta induced by sensory (tail pinch) or chemical stimulation (carbachol), suggesting that the presence of the theta state regardless of how it was produced was responsible for the reduction in epileptic discharge frequency. The understanding of the theta rhythm "anti-epileptic" effect at the cellular and molecular levels may result in novel therapeutic approaches dedicated to protect the brain against abnormal excitability states.     

Hippocampal network patterns of activity in the mouse

Genetic engineering of the mouse brain allows investigators to address novel hypotheses in vivo. Because of the paucity of information on the network patterns of the mouse hippocampus, we investigated the electrical patterns in the behaving animal using multisite silicon probes and wire tetrodes. Theta (6-9 Hz) and gamma (40-100 Hz) oscillations were present during exploration and rapid eye movement sleep. Gamma power and theta power were comodulated and gamma power varied as a function of the theta cycle. Pyramidal cells and putative interneurons were phase-locked to theta oscillations. During immobility, consummatory behaviors and slow-wave sleep, sharp waves were present in cornu ammonis region CA1 of the hippocampus stratum radiatum associated with 140-200-Hz "ripples" in the pyramidal cell layer and population burst of CA1 neurons. In the hilus, large-amplitude "dentate spikes" occurred in association with increased discharge of hilar neurons. The amplitude of field patterns was larger in the mouse than in the rat, likely reflecting the higher neuron density in a smaller brain. We suggest that the main hippocampal network patterns are mediated by similar pathways and mechanisms in mouse and rat.     

Striatal and septal influence on hippocampal theta and spikes in the cat

The experiments studied the modulation exerted by the septum and the caudate nucleus on hippocampal activity in the cat. Injections (i.v.) of sodium penicillin were performed in order to obtain a steady interictal epileptic activity. Hippocampal slow rhythmic activity showed a marked decrease either in duration or in frequency following penicillin activation. Both septal and caudate electrical stimulation inhibited spike frequency through a theta eliciting mechanism. Caudate stimulation failed to determine any sort of effect after medial septum lesions. The importance of the septum as modulation station between basal ganglia and hippocampus is emphasized.     

Modifications of bioelectrical activity of the hippocampus of mice induced by acetoxycycloheximide (author's transl)

Swiss male mice were chronically implanted with electrodes in dorsal hippocampus and in mesencephalon (mesencephalic reticular formation and central gray). Effects of acetoxycycloheximide (AXM) on spontaneous bioelectrical activity of the hippocampus and on hippocampal response to mesencephalic stimulation were analyzed. AXM injection (7 mg/kg) provoked a decrease in both frequency and amplitude of the spontaneous hippcampal activity and, in particular, a marked decrease in the theta activity in the 6–10 cps band. AXM induced no change in the mesencephalic stimulation threshold shown to induce hippocampal theta rhythm. A decrease in both frequency and amplitude of the theta rhythm induced by mesencephalic stimulation was, however, recorded. These alterations, which appeared during the first hour following AXM injection, were especially obvious from 3 to 6 hours after treatment. From 7 to 24 hours after injection, the hippocampal bioelectrical activity, either spontaneous or induced, recovered gradually its initial characteristics.     

The spontaneous activity of hippocampal neurons during the modulation of theta rhythm by cholinergic substances

A statistical analysis of the baseline activity of neurons, recorded intracellularly in the hippocampus of awake, nonimmobilized rabbits in three states, control and during the systemic administration of eserine and scopolamine, was carried out. Neurons of the hippocampus were additionally tested in a similar manner following the chronic basal undercutting of the septum, removing stem influences. The cholinergic substances regulate the number of neurons of the hippocampus having theta modulation and the degree of its stability, but do not influence its frequency. When the cholinergic theta rhythm is activated, regularization of the activity takes place with the suppression of delta modulation and of complex spikes; its blockade is accompanied by the opposite changes. Both substances stably alter the level of the baseline frequency of discharges of the majority of neurons, although the total average frequency remains constant. Regression analysis shows the predominance of a decrease in the activity in highfrequency (> 25 spikes/sec) and an increase in the lowf-requency (< 25 spikes/sec) neurons during the effect of both substances. The constancy of the total average frequency and the unidirectionality of the shifts in the level of discharges of the neurons during the intensification (eserine) and blockade (scopolamine) of the cholinergic component of the theta rhythm points to the fact that the cholinergic septal input directly influences mainly the structure but not the level of the activity of the hippocampal neurons.Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 42, No. 5, pp. 944–954, September–October, 1992.     

A feature of caudate control of focal hippocampal epilepsy: evidence for an anterograde pathway

Summary Previous experimental evidences showed that the caudate nucleus has a modulatory effect on hippocampal epilepsy. The caudate's regulating action might reach the hippocampus either via the septal region or, retrogradely, via the accumbens nucleus. In order to obtain new data about the pathway involved in caudate hippocampal influence the spreading of abnormal activity towards the nucleus accumbens was studied. Furthermore the effects of caudate stimulation in animals with electrolytic lesions of the nucleus accumbens were analyzed. It was observed that abnormal penicillin-induced activity spreaded from the hippocampus to the nucleus accumbens in about 30 minutes. In animals with and without lesions of nucleus accumbens, caudate stimulation brought about a significant decrease in the frequency and amplitude of hippocampal activity. The results suggest that the nucleus accumbens is reached by the spreading of hippocampal epilepsy but does not participate in the control exerted by the caudate nucleus on the hippocampus. Thus the caudate-induced inhibition takes place through an anterograde caudate-hippocampal circuit, while at the same time excluding retrograde activation by way of a caudate-accumbens-hippocampal pathway.     

Long-term synaptic plasticity in deep layer-originated associational projections to superficial layers of rat entorhinal cortex

Superficial layers of the entorhinal cortex (EC) relay the majority of cortical input projections to the hippocampus, whereas deep layers of the EC mediate a large portion of hippocampal output projections back to other cortical areas, suggesting a functional segregation between superficial and deep layers of the EC as input and output structures of the hippocampus, respectively. However, deep layers of the EC send associational projections to superficial layers, suggesting a potential interaction between neocortical input and hippocampus-processed output in superficial layers. This possibility was investigated by examining whether deep to superficial EC projections support long-term synaptic plasticity, and whether they interact with other pathways in superficial layers in rat medial EC slice preparations. Synaptic responses of the deep-to-superficial layer projections were verified based on field potential profiles, paired-pulse facilitation, physical separation between superficial and deep layers, and pharmacological manipulation. Long-term potentiation (LTP) was reliably induced in the deep-to-superficial layer projections by burst stimulations that emulated theta or sharp wave electroencephalogram (EEG),and it was blocked by an N-methyl-d-aspartate receptor antagonist (D-2-amino-5-phosphonopentanoic acid) and a calcium channel blocker (nifedipine). Prolonged low frequency stimulation induced long-term depression. A weak stimulation of deep layers, which induced a small degree of LTP by itself, generated a much larger degree of LTP when paired with a strong stimulation of superficial layers, indicating that the deep-to-superficial layer projections cooperate with other pathways in the superficial EC to enhance synaptic weights. Our results suggest that neocortical input and hippocampal output information are integrated in superficial layers of the EC.     

Spontaneous activity and sensory responses of hippocampal neurons during persistent theta-rhythm evoked by median raphe nucleus blockade in rabbit

Spontaneous activity and responses to sensory stimuli were analysed in the hippocampal CA1 neurons of chronic unanesthetized rabbits before and after reversible functional blockade of the median raphe nucleus and medial septal area by local microinjections of anesthetic lidocaine. This evoked, correspondingly, persistent theta rhythm and its complete blockade for about 30 min. The results were compared to the neuronal data obtained earlier in the experiments with cholinergic drugs modulating expression of theta rhythm. Intra-median raphe nucleus injection of lidocaine evoked uniform increase of discharge rate in the hippocampal neurons with low and high spontaneous activity. Theta modulation of neuronal activity had increased regularity and frequency (by 0.5-2.0 Hz) and appeared in additional group of the neurons simultaneously with expression of persistent theta in the hippocampal electroencephalogram. Sensory responsiveness of the hippocampal neurons was drastically decreased (45% of the responses preserved). Reactions of all types were blocked, diminished, or inverted, but inhibitory responses were the most severely affected. Injection of lidocaine into medial septal area also blocked all brain stem afferents ascending to the hippocampus via medial septal area, thus, totally depriving hippocampus of brainstem-septal input. However, besides the total absence of theta modulation, spontaneous activity in majority of neurons was not significantly changed. Responsiveness to sensory stimuli also remained relatively high (77% of the responses preserved); on-effects were especially resistant to medial septal area blockade. Comparison of spontaneous and evoked activity in two theta states (physostigmine and median raphe nucleus blockade) revealed striking similarity of all characteristics, which suggested that theta-suppressing influences of median raphe nucleus (presumably serotonergic) are realized primarily through the control of cholinergic septo-hippocampal theta-generating mechanism. However, as the frequency of theta rhythm does not depend on it, an additional effect of disinhibition of activating reticular formation by the median raphe nucleus suppression is suggested. The data confirm that theta rhythm may be regarded as active filter in the information processing by the hippocampal neurons.     

Expression, control, and probable functional significance of the neuronal theta-rhythm

The data on theta-modulation of neuronal activity in the hippocampus and related structures, obtained by the author and her colleagues have been reviewed. Analysis of extracellularly recorded neuronal activity in alert rabbits, intact and after various brain lesions, in slices and transplants of the hippocampus and septum allow one to make the following conclusions. Integrity of the medial septal area (MS-DB) and its efferent connections are indispensable for theta-modulation of neuronal activity and EEG of the hippocampus. The expression of hippocampal theta depends on the proportion of the MS-DB cells involved in the rhythmic process, and its frequency in the whole theta-range, is determined by the corresponding frequencies of theta-burst in the MS-DB. The neurons of the MS-DB have the properties of endogenous rhythmic burst and regular single spike oscillators. Input signals ascending to the MS-DB from the pontomesencephalic reticular formation increase both the frequency of the MS-DB theta-bursts and the proportion of neurons involved in theta-activity; serotonergic midbrain raphe nuclei have the opposite effect on the MS-DB rhythmic activity and hippocampal EEG theta. Increase of endogenous acetylcholine (by physostigmine) also increases the proportion of the MS-DB neurons discharging in theta-bursts (both in intact and basally-undercut septum), but does not influence the theta-frequency. The primary effect of the MS-DB on hippocampal neurons (pyramidal and non-pyramidal) consists in GABAergic reset inhibition. Reset inhibition, after which theta-modulation follows in constant phase relation, is triggered also by sensory stimuli. About two-thirds of the hippocampal pyramidal neurons are tonically inhibited by sensory stimuli which evoke EEG theta, while others are excited, or do not change their activity. Anticholinergic drugs restrict the population of rhythmic neurons but do not completely suppress theta-bursts in the MS-DB and hippocampus. Under their action, EEG theta can be evoked (presumably through GABAergic MD-DB influences) by strong reticular or sensory stimuli with corresponding high frequency. However information processing in this condition is defective: expression of reset is increased, responses to electrical stimulation of the perforant path and to sensory stimuli are often augmented, habituation to sensory stimuli is absent and tonic responses are curtailed. On a background of continuous theta induced by increase of endogenous acetylcholine, reset is absent or reduced, responsiveness of the hippocampal neurons to electrical and sensory stimulation is strongly reduced. It is suggested that the theta-rhythm has a double function in information processing: it facilitates and prolongs the action of the stimuli entering the hippocampus in phase with concomitantly triggered theta (‘filtering in’), and it prevents the admission of signals appearing during on-going theta triggered by a previous event (“filtering out”), eliminating interference during processing and registration of information. Thus, the theta-rhythm may be regarded as a mechanism of selective attention, a prerequisite for memory trace formation.     

Septo-hippocampal connections and the hippocampal theta rhythm

Summary Recordings were made of spontaneous hippocampal theta activity in free-moving rats, before and after a variety of lesions. Three recording sites were used to monitor activity in the dorsal hippocampus, the ventral hippocampus, or close to the site of the hippocampal flexure. Electrolytic lesions were made in the medial septal area or the dorso-lateral septal area; surgical transections were made of the fimbria or dorso-medial area of the fornix. Following lesions restricted to the medial septal area, theta was abolished throughout the hippocampus; after lesions restricted to the dorso-lateral septal area theta was retained. Fimbria lesions abolished theta in the ventral, but not the dorsal hippocampus; dorso-medial fornix lesions abolished it in the dorsal, but not the ventral, hippocampus. In some subjects the hippocampal formation was subsequently stained for cholinesterase: cholinesterase staining loss was generally associated with theta loss, but this was not clear at the flexure recording site. It was confirmed that theta is dependent upon the integrity of the medial septal area. It was concluded that damage to hippocampal afferents from the septum does abolish theta, while damaging the feedback efferents does not.     

Firing relations of lateral septal neurons to the hippocampal theta rhythm in urethane anesthetized rats

Summary The firing of lateral septal neurons was examined in relation to the hippocampal theta rhythm in urethane anesthetized rats. In general, the firing rates of these cells were low during both theta and non-theta EEG states. There was no significant change in firing rate between the two states (theta: 8.5±9.9 spks/sec; non-theta: 6.0±5.3). Sixty-four of 68 cells fired simple spikes and 4 cells were found to fire bursts of action potentials (complex-spikes). Approximately 30% (21/65) of the cells showed a significant phase relation to the hippocampal theta rhythm. The preferred phases of firing of these 21 cells were broadly distributed. The possibility that the phase-locked firing of LSN cells is due to the phase-locked firing of hippocampal projection cells is discussed.     

Behavioral, electroencephalographic and histopathological studies on mongolian gerbils with occluded common carotid arteries

The effect of brain ischemia on passive avoidance test was investigated in mongolian gerbils with ischemia induced by a 5 min bilateral occlusion of the carotid arteries. Severe impairment of memory was apparent when the training session of the passive avoidance test was carried out 2 or 14 days after the bilateral ischemia. Two days after the occlusion, the amplitude of hippocampal theta waves were slightly decreased and Nissl's degradation was apparent in the CA1 neurons in the hippocampus. The changes in hippocampal neurons become progressively more severe. The amplitude of the hippocampal theta waves diminished considerably and the CA1 neurons in the hippocampus disappeared 14 days after the occlusion. We suggest that the hippocampal damage, especially abnormalities in the CA1 neurons, evidenced by histopathological and electroencephalographic results, may be related to deficits in memory following bilateral common carotid arteries occlusion.     

Selective blockade of excitatory caudate responses to nigral stimulation by microiontophoretic application of dopamine antagonists

The dopamine (DA) antagonists haloperidol (Hal), chlorpromazine (CPZ) and fluphenazine (Flu) were applied by microiontophoresis from 8-barreled micropipettes while action potentials were recorded from single neurons in the feline caudate nucleus (CN) which fired in response to afferent stimulation. These DA antagonists selectively blocked the 15--25 msec latency action potential elicited by stimulation of the substantia nigra (SN) without affecting responses to cortical or thalamic stimulation. These results suggest that dopamine is the transmitter of the excitatory response of caudate neurons to stimulation of the SN. No evidence for an inhibitory input to the caudate liberating DA was found.     

The Serotonin Reuptake Inhibitor Fluoxetine Suppresses Theta Oscillations in the Electroencephalogram of the Rabbit Hippocampus

Our previous studies on conscious rabbits showed that stimulation of the median cervical nucleus (MCN) decreases the extent and frequency of oscillatory theta activity in the septohippocampal system, while functional blockade of the nucleus by administration of the anesthetic lidocaine produces a stage high-frequency theta rhythm. The present study addresses the nature of the serotoninergic influences of the MCN (which also contains cells of other chemical natures) on the septohippocampal system. Experiments on conscious rabbits involved recording of the hippocampal EEG in control conditions and after microinjection of fluoxetine, a serotonin reuptake blocker which increases the levels of this transmitter in the brain. In all experiments, bilateral intracerebroventricular administration of fluoxetine hydrochloride (Sigma, St. Louis, MO; 15 microg in 5 microl of physiological saline) induced decreases in the magnitude of the hippocampal theta rhythm. In 15 of 18 (83.3%) of experiments, suppression of the oscillator activity by at least 50% of control was seen. The amplitude of the theta band in the spectral density histogram decreased by an average of 56 +/- 5.8% compared with control values (decreases in different experiments were from 7% to 90% of control p < 0.001). The latent period of these changes averaged 3.5 +/- 0.11 min (range: 2.9-4.1 min). The effect lasted 64.8 +/- 3.2 min (varying from 45.3 to 90 min in different experiments). There were no significant changes in the theta rhythm frequency, as compared with controls; this averaged 5.25 +/- 0.5 Hz (range: 4.5-6.5 Hz). The decrease in the magnitude of theta oscillations in the hippocampus after administration of fluoxetine provided evidence of the inhibitory control of rhythmic theta activity by the serotoninergic system of the brain.     

Dorsal raphe neurons: synchronous discharge with the theta rhythm of the hippocampus in the freely behaving rat.

1. Single-unit activity of 30 dorsal raphe (DR) neurons was recorded along with the cortical and hippocampal electroencephalogram and neck muscle electromyogram in freely behaving rats during sleep-waking states. 2. On the basis of firing rates, DR cells were divided into slow-firing (S-cells), fast firing (F-cells), and very fast firing (FF-cells) units. The S-cells (8 units) fired at rates of < 10 Hz, the F-cells (11 units) at 10-40 Hz, and the FF-cells (11 units) at 55-70 Hz. 3. The activity of 17 of 30 DR units was correlated with the theta rhythm of the hippocampus. They included both slow and rapidly firing DR neurons. These cells typically fired irregularly (single spikes or short-duration bursts of activity) during non-theta states of quiet waking and slow-wave sleep. With the change of behavioral state to awake-moving or rapid eye movement sleep, the activity of these units switched to a regular bursting pattern synchronous with the hippocampal theta rhythm. Seven of these 17 units were classified as theta-rhythmic cells on the basis of the tight phase-locking of their discharge to the hippocampal theta rhythm. The remaining 10 units were classified as theta-modulated cells on the basis of a smaller but significant coherence between unit discharge and the theta rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hippocampal evoked field potentials and interictal spikes in hippocampally kindled cats.

Kindling-related changes of the hippocampal evoked field potentials and patterns of the spontaneous interictal spikes were investigated in 10 hippocampally kindled cats. A complex potential waveform was recorded by macroelectrodes placed in the CA3 region of the hippocampal gyrus and hilus of the gyrus dentatus, close to the granule cell layer, after stimulation of the entorhinal cortex. After high intensity repetitive (10/s) stimulation a late component could be recorded with the latency of about 30-40 ms, in addition to the early response originating in the gyrus dentatus. Probably this component developed during kindling into a delayed, high amplitude spike. After application of the double shock test, post-stimulus facilitation of the spike response was observed within time limits of 20-100 ms. Another observation was a widespread, ipsilateral and bilateral long-term enhancement of the amplitudes of field potentials evoked by entorhinal and intrahippocampal stimulation. It was the most common effect observed during kindling. Widespread synchronized discharges of hippocampal spikes and localized clusters of brief irregular spikes were the most significant features of spontaneous interictal spikes. The paroxysmal discharges of spikes could be evoked by ipsi or by contralateral stimulation of the afferent pathways projecting to the kindled hippocampus, rather than by direct electrical stimulation of the kindled hippocampal gyrus.     

Background activity of rabbit hippocampal neurons in conditions of functional exclusion of structures which regulate the theta rhythm

The functional importance of theta modulation in the activity of hippocampal neurons was further analyzed using a method consisting of controlled sequential short-term (25–30 min) inclusion or exclusion of the theta rhythm by local administration of lidocaine into the median cervical nucleus and medial septal region respectively. Studies were carried out using conscious rabbits with extracellular recording of hippocampal neuron activity in field CA1. Administration of lidocaine into the medial septal nucleus and diagnoal tract nucleus (MS-DT) led to complete inhibition of theta modulation in neuronal and total hippocampus activity. The mean frequency of background discharges underwent no change in most neurons, but decreased significantly in a limited group of cells with high-frequency activity (presumptive inhibitory neurons). Administration of lidocaine into the median cervical nucleus (MCN), the source of serotoninergic pathways to the MS-DT and hippocampus, was accompanied by increases in the stability and frequency of theta modulation of neuronal activity, induction of theta modulation in an additional group of neurons, and expression of a continuous theta rhythm in the electrical activity (EA) of the hippocampus. The mean frequency and regularity of discharges increased in most cells. These data support the existence of tonic inhibitory effects on the part of the MCN on the septa-hippocampal system generating the theta rhythm; in this regard, the MCN can be regarded as an antagonist of the activating reticular formation. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 48, No. 3, pp. 505–515, May–June, 1998.     

A review of hippocampal activation in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is often characterized by deficits in memory encoding and retrieval and aberrant fear and extinction learning. The hippocampus plays a critical role in memory and contextual processing and has been implicated in intrinsic functional connectivity networks involved in self-referential thought and memory-related processes. This review focuses on hippocampal activation findings during memory and fear and extinction learning tasks, as well as resting state hippocampal connectivity in individuals with PTSD. A preponderance of functional neuroimaging studies to date, using memory, fear learning, and extinction tasks, report decreased or “controls comparable” hippocampal activation in individuals with PTSD, which is usually associated with poorer performance on the task imaged. Existing evidence thus raises the possibility that greater hippocampal recruitment in PTSD participants may be required for similar performance levels. Studies of resting state functional connectivity in PTSD predominantly report reduced within-network connectivity in the default mode network (DMN), as well as greater coupling between the DMN and salience network (SN) via the hippocampus. Together, these findings suggest that deficient hippocampal activation in PTSD may be associated with poorer performance during memory, extinction recall, and fear renewal tasks. Furthermore, studies of resting state connectivity implicate the hippocampus in decreased within-network DMN connectivity and greater coupling with SN regions characteristic of PTSD.