Jesse Jackson

Nonserotonergic projection neurons in the midbrain raphe nuclei contain the vesicular glutamate transporter VGLUT3

The brainstem raphe nuclei are typically assigned a role in serotonergic brain function. However, numerous studies have reported that a large proportion of raphe projection cells are nonserotonergic. The identity of these projection cells is unknown. Recent studies have reported that the vesicular glutamate transporter VGLUT3 is found in both serotonergic and nonserotonergic neurons in both the median raphe (MR) and dorsal raphe (DR) nuclei. We injected the retrograde tracer cholera toxin subunit B into either the dorsal hippocampus or the medial septum (MS) and used triple labeled immunofluorescence to determine if nonserotonergic raphe cells projecting to these structures contained VGLUT3. Consistent with previous studies, only about half of retrogradely labeled MR neurons projecting to the hippocampus contained serotonin, whereas a majority of the retrogradely labeled nonserotonergic cells contained VGLUT3. Similar patterns were observed for MR cells projecting to the MS. About half of retrogradely labeled nonserotonergic neurons in the DR contained VGLUT3. Additionally, a large number of retrogradely labeled cells in the caudal linear and interpeduncular nuclei projecting to the MS were found to contain VGLUT3. These data suggest the enigmatic nonserotonergic projection from the MR to forebrain regions may be glutamatergic. In addition, these results demonstrate a dissociation between glutamatergic and serotonergic MR afferent inputs to the MS and hippocampus suggesting divergent and/or complementary roles of these pathways in modulating cellular activity within the septohippocampal network. Synapse 63: 31–41, 2009.

Median Raphe Stimulation Disrupts Hippocampal Theta Via Rapid Inhibition and State-Dependent Phase Reset of Theta-Related Neural Circuitry

Evidence has accumulated suggesting that the median raphe (MR) mediates hippocampal theta desynchronization. However, few studies have evaluated theta-related neural circuitry during MR manipulation. In urethane-anesthetized rats, we investigated the effects of MR stimulation on hippocampal field and cell activity using high-frequency (100 Hz), theta burst (TBS), and slow-frequency electrical stimulation (0.5 Hz). We demonstrated that high-frequency stimulation of the MR did not elicit deactivated patterns in the forebrain, but rather elicited low-voltage activity in the neocortex and small-amplitude irregular activity (SIA) in the hippocampus. Both hippocampal phasic theta-on and -off cells were inhibited by high-frequency MR stimulation, although MR stimulation failed to affect cells that had neither state or phase relationships with theta field activity. TBS of the MR-induced theta field activity phase locked to the stimulation. Slow-frequency stimulation elicited a state-dependent reset of theta phase through a short-latency inhibition (5 ms) in phasic theta-on cells. Subpopulations of phasic theta-on cells responded in either oscillatory or nonoscillatory patterns to MR pulses, depending on their intraburst interval. off cells exhibited a state-dependent modulation of cell firing occurring preferentially during nontheta. The magnitude of MR-induced reset varied as a function of the phase of the theta oscillation when the pulse was administered. Therefore high-frequency stimulation of the MR appears to disrupt hippocampal theta through a state-dependent, short-latency inhibition of rhythmic cell populations in the hippocampus functioning to switch theta oscillations to an activated SIA field state.

Functional brain mapping at 9.4T using a new MRI-compatible electrode chronically implanted in rats

There is a need for acute and chronic stimulation of the brain within the MRI for studies of epilepsy, as well as deep brain stimulation for movement and behavioral disorders. This work describes the production and characteristics of carbon fiber–based electrodes for acute and chronic stimulation in the brain. Increasing MRI field strengths are making it increasingly difficult to introduce foreign objects without a susceptibility artifact. We describe the production of, and the characteristics of carbon fiber–based electrodes. These are biocompatible and can be implanted for chronic studies. We show the use of these electrodes at 9.4T for studying functional activation. Data are presented showing regional connectivity. Activation not only occurs near the electrode, but at sites distant and often contralateral to the electrode. In addition, there were sites showing strong negative activation to stimulation both with direct stimulation and during a kindling‐associated seizure. Magn Reson Med 61:222–228, 2009.

Dissociable pathways facilitate theta and non‐theta states in the median raphe—Septohippocampal circuit

Hippocampal theta rhythms in vivo are modulated by a synchronizing projection from the medial septum (MS) and a desynchronizing input from the median raphe nucleus (MRn) of the brainstem. Inactivation of the MS suppresses theta rhythms while inactivation of the median raphe produces persistent theta. However, different pathways arise from within the MS and the median raphe and therefore different brain states could be facilitated by different forms of median raphe or septohippocampal inputs. Here, we found in urethane anesthetized rats that suppression of outputs from the MRn with procaine leads to persistent hippocampal theta as previously reported. The discharge properties of hippocampal theta‐related cells recorded during both spontaneously occurring theta and MRn 8‐OH‐DPAT‐induced theta did not differ significantly. This persistent theta was abolished by inactivation of the MS with either procaine or atropine sulfate. Selective inactivation of serotonergic median raphe outputs with the 5‐HT‐1A agonist (8‐OH‐DPAT) induced theta that was also abolished by medial septal inactivation using procaine. Thus, persistent theta following complete median raphe inactivation or selective serotonergic inactivation arises from a median raphe to MS pathway. However, 8‐OH‐DPAT infusions into the median raphe together with atropine infusions in the MS did not abolish theta activity. These data suggest that the non‐serotonergic (possibly glutamatergic) median raphe projections to the MS can facilitate the generation of hippocampal theta in the absence of medial septal cholinergic tone. These results demonstrate that dissociable neuronal pathways in the median raphe–MS–hippocampal circuit promote different brain states (theta or non‐theta) and a median raphe non‐serotonergic (likely glutamatergic) system may serve a separate function from the ascending serotonergic raphe projection in the regulation of hippocampal network activity.

To move or not: previous experience in a runway avoidance task determines the appearance of hippocampal Type 2 sensory processing theta.

Rats in a runway avoidance task responded to a test shock probe with a period of immobility lasting from 2 to 6s. The shock avoidance-trained group displayed hippocampal theta during the immobility response. The inescapable shock group, in contrast, displayed large amplitude irregular activity (LIA). Following reversal training to escapable shock, all shock avoidance-trained rats responded with LIA and inescapable shock trained rats, reversed to shock avoidance, displayed theta.

High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy

Deep brain stimulation (DBS) of the subthalamic nucleus has been used extensively in the treatment of Parkinsons disease. However, the efficacy of such treatments on bradykinesia/akinesia remains low. DBS of the posterior hypothalamic nucleus (PH) elicits spontaneous, non-stereotypical motor behaviours. We tested the hypothesis that PH stimulation could restore movement in animals made cataleptic by the D(2) receptor antagonist haloperidol. We further hypothesized that hippocampal-striatal neural synchrony may be important in the organization of motor behaviours. Animals chronically implanted with hippocampal and striatal recording electrodes and PH stimulating electrode were tested in open field, catalepsy and active avoidance paradigms. The degree of hippocampal-striatal theta (5-10 Hz) field coherence was assessed during baseline avoidance testing and following the administration of haloperidol. Haloperidol abolished movement in open field and active avoidance tasks and increased the latency to respond in the catalepsy test. Stimulation of the PH under haloperidol reversed catalepsy. Hippocampal-striatal theta coherence was high throughout the active avoidance task in control experiments but was greatly reduced under haloperidol. PH stimulation was able to reinstate the hippocampal-striatal theta coherence while restoring task-related behaviours. These results support the hypothesis that DBS of the PH could restore motor behaviours in rats made cataleptic with haloperidol, thus providing strong support for the PH as a promising candidate for DBS in the treatment of Parkinsons disease. Furthermore, the results support the view that hippocampal-striatal theta coherence may be important for the planning and execution of goal-oriented behaviors.

Decoupling of Acetylcholine Influx and Theta Power in the Hippocampus

The importance of acetylcholine (ACh) in higher cognitive functions has been postulated for decades ([Sarter et al., 2005][1]). Attention, arousal, novelty detection, and learning all rely on an intact cholinergic system, which arises principally from the nucleus basalis and the medial septum.