Restoration of mammillothalamic functional connectivity through thiamine replacement therapy in Wernicke's encephalopathy.

Resting-state functional MRI (fMRI) is now providing further understanding of neuropsychiatric illnesses. However, its practical applicability in the clinical realms is still questionable. Here we report three consecutive followed-up resting-state fMRI data in a single case with Wernicke encephalopathy before and after high-dose thiamine replacement therapy ranging over 20 months. We measured the mammillothalamic functional connectivity strength between the first ROI (mammillary body) and a voxel which showed the highest co-activation among voxels within the anterior thalamus (the second ROI) to enhance the specificity of the functional connectivity data. We found that the time-series changes in the mammillothalamic functional connectivity generally paralleled to the changes in delayed verbal and nonverbal recall memory scores in the left and right hemisphere, respectively. Among these, the left-side connectivity and delayed verbal recall score seemed to be related to the overall clinical status change. Modified directed transfer function (dDTF) analysis also identified significant information flows with mammillary-to-thalamic direction except at the acute illness state. Our findings, though preliminary in nature, suggest the practical applicability of resting-state fMRI to trace an effect of thiamine replacement therapy on the memory tract function in Wernicke encephalopathy at single-patient level.

The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats.

RATIONALE: Ketamine or MK-801 induced sensorimotor gating deficit, but the underlying neural mechanisms are not completely known. We have previously demonstrated that the medial septum (MS) mediated the phencyclidine-induced deficit in prepulse inhibition of the acoustic startle (PPI) in rats. OBJECTIVES: We investigated the involvement of the supramammillary area (SUM) to MS pathway in PPI impairment and behavioral hyperlocomotion induced by MK-801 or ketamine in rats and correlated the behavioral deficits with hippocampal gamma wave increase. MATERIALS AND METHODS: Ketamine (6 mg/kg, s.c.) or MK-801 (0.5 mg/kg, i.p.) was administered after infusion of saline or the GABA(A) receptor agonist, muscimol (0.25 microg), into the MS or SUM. Locomotion, PPI, and hippocampal electroencephalogram (EEG) were recorded. RESULTS: MK-801 or ketamine induced PPI impairment and behavioral hyperlocomotion, accompanied by an increase in hippocampal gamma waves (30-100 Hz). The changes in behavior and gamma waves induced by ketamine or MK-801 were antagonized by pre-infusion of muscimol, but not saline, into the SUM or MS. Infusion of muscimol into the SUM alone did not significantly affect PPI, but it suppressed spontaneous locomotor behavior and hippocampal EEG. Infusion of ionotropic glutamate receptor antagonists into the MS did not affect the PPI deficit or the gamma wave increase after MK-801. CONCLUSIONS: A non-glutamatergic component of the supramammillo-septal pathway mediates the hyperlocomotion and the deficits in PPI induced by MK-801 or ketamine. Inactivation of the MS or SUM normalized both the hippocampal gamma waves and the behavioral deficits (PPI impairment and hyperlocomotion).

The role of the medial supramammillary nucleus in the control of hippocampal theta activity and behaviour in rats.

The medial supramammillary nucleus (mSUM) controls the frequency of hippocampal theta activity, completely in anaethsetized rats and partially in free-moving rats. mSUM could therefore influence hippocampal contributions to cognition and emotion. Using chemical lesions of mSUM in rats, we tested whether mSUM is involved in controlling several hippocampal-dependent functions: (i) defensive behaviour (open field, fear conditioning); (ii) behavioural inhibition (fixed interval schedule, differential reinforcement of low rates schedule); and (iii) spatial learning (water maze). Theta frequency was measured in all these tasks. mSUM lesions produced a pattern of changes in motivated/emotional behaviours (hyperactivity in defensive and operant tasks) similar to the pattern produced by hippocampal lesions, but had no significant effect on spatial learning. mSUM lesion decreased theta frequency modestly (by approximately 0.4 Hz) in behaving rats if the amount of movement was unchanged. There was not always a parallel between changes in theta frequency and behaviour; behaviours changed despite unchanged theta in defensive tasks and learning changed little despite a lower frequency of theta in the water maze task. This suggests that mSUM function impacts on emotional behaviour more than cognition, and can modulate theta and behaviour independently.

Opposite modulation of histaminergic neurons by nociceptin and morphine.

We have studied the effects of nociceptin/orphanin FQ on the histaminergic neurons in the tuberomammillary (TM) nucleus and compared them with the actions of opioid agonists. Intracellular recordings of the membrane potential were made with sharp electrodes from superfused rat hypothalamic slices. Nociceptin strongly inhibited the firing of the TM neurons. In the concentration range 10-300 nM, nociceptin hyperpolarized the neurons in a dose-dependent and reversible manner. Insensitivity to tetrodotoxin indicated a postsynaptic effect which was associated with decreased input resistance. Voltage-current plots suggested the involvement of a potassium conductance which was highly sensitive to Ba(2+) and decreased by Cs(+), in keeping with the activation of an inwardly rectifying potassium channel. Morphine (20-100 microM) depolarized the TM neurons and increased their firing, and this effect was blocked by tetrodotoxin. Dynorphin A(1-13) at 100-300 nM did not affect the TM neurons. Nociceptin and morphine modulate the activity of the TM neurons, and most likely histamine release, in opposite ways. Histamine has an antinociceptive effect in the brain and may be involved in opioid-induced analgesia. Nociceptin might therefore influence pain transmission by inhibiting opioid-induced histamine release from the TM nucleus and also modulate other physiological mechanisms which have been ascribed to the histaminergic system.

[The effect of electrostimulation of the hypothalamic mamillary nuclei on the vascular permeability of the skin in intact and capsaicin-pretreated rats]. / Vliianie élektrostimuliatsii mamilliarnykh iader gipotalamusa na pronitsaemost' sosudov kozhi u intaktnykh i predvaritel'no obrabotannykh kapsaitsinom krys.

Electrical stimulation of the hypothalamic mamillary nuclei increased the permeability of the skin blood vessels in rats. Pretreatment of the animals with capsaicin prevented the effect. The mamillary nuclei seem to take part in the central mechanisms of efferent function of the capsaicin-sensitive neurons.

Fos-like immunoreactivity in the mamillary body and thalamus following injections of muscimol into the ventral tegmental nucleus of Gudden in the rat.

In many neurons, increased rates of firing are accompanied by expression of the proto-oncoprotein Fos. The current study examined Fos-like immunoreactivity in the mamillary body and the anterior thalamus following unilateral injections of the inhibitory GABA-A agonist muscimol into the ventral tegmental nucleus of Gudden (VTN). These injections resulted in a marked increase in Fos-like immunoreactivity ipsilaterally in both the medial mamillary nucleus and in its principle thalamic projection targets, the anteroventral and anteromedial thalamic nuclei. Since the projection from the VTN to the mamillary body has been shown to contain a substantial GABAergic component, these results are likely to reflect a disinhibition of mamillothalamic circuitry resulting from suppression of tonic inhibitory inputs arising in the VTN.

Alteration of cortical and hippocampal cholinergic activities following lesion of the mammillary bodies in mice.

The effects of ibotenic acid lesions of the mammillary bodies (MM) on the sodium-dependent high affinity choline uptake (SDHACU) velocity into both the hippocampus and the frontal cortex were investigated in this study in either a quiet or an active (exploration of a T-maze) condition. Results showed that MM lesion globally produced a significant decrease of both hippocampal and cortical SDHACU. However, the magnitude of this decrease was not significantly different in the active as compared to the quiet condition. These findings suggest that MM lesion alters the tonically but not phasically active transynaptic control of cortical and hippocampal cholinergic activities.

Effects of chronic ethanol consumption associated or not with experimental anterior thalamic lesions on spontaneous sequential alternation in mice.

Previous studies from our team have shown that a 12 month ethanol administration induced deficits in a sequential alternation task, whereas a 6 month treatment had no effects. We have already shown that the 12 month treatment induced deficits both in diencephalic and hippocampal structures, whereas the 6 month treatment damaged only the mammillary bodies. Thus, the question remained whether or not increasing selectively the diencephalic damage by lesioning the anterior thalamic nuclei would disrupt sequential alternation in 6 month ethanol-treated mice. Results indicate that alcohol-treated mice exhibiting experimental lesions into the anterior thalamus were significantly impaired in the sequential task as compared to both controls or 6 month ethanol-treated mice. In contrast, anterior thalamic lesions in normal (no alcohol treatment) subjects induced no deficits. The relative contribution of the hippocampo-mammillo-thalamic circuitry in sequential alternation is discussed.

Facilitation of sexual receptivity by hypothalamic and midbrain implants of progesterone in female hamsters.

In the first experiment, ovariectomized female hamsters were stereotaxically implanted with bilateral guide cannulae aimed at the medial preoptic area (POA), ventromedial hypothalamus (VMH), or ventral tegmentum (VTA). The following week these females were injected SC with 10 micrograms estradiol benzoate (EB) and then had 27-gauge cannulae containing crystalline progesterone inserted through the guide tubes. Sexual receptivity was observed in 3 of 11 animals with VMH implants of progesterone, in 2 of 10 with VTA progesterone, but in none with POA implants. In the second experiment, the amount of intracranial progesterone was increased by mechanically expelling a 1.5 micrograms progesterone pellet from the tip of each cannula insert. This treatment facilitated receptivity in 10 of 20 hamsters with VTA implants and in 9 of 32 VMH-implanted animals. This induction of receptivity required approximately 2 hr. Progesterone pellets in the POA, mammillary region, and lateral mesencephalon were generally ineffective. In hamsters, progesterone into either the VMH or the VTA is sufficient to facilitate receptivity, although neither site is highly sensitive to progesterone. These results differ from those in recent studies in rats and this difference may reflect important species differences in the control of lordosis.

[Bioelectric activity of the hypothalamus of adult and old rabbits during prolonged vasopressin administration]. / Bioélektricheskaia aktivnost' gipotalamusa vzroslykh i starykh krolikov pri dlitel'nom vvedenii vazopressina.

In adult and old rabbits, the bioelectrical activity of supraotic, ventromedial and mamillary hypothalamic nuclei was studied after chronic (30 days) administration of vasopressin (0.2 U/kg of body weight). The hormone altered considerably the bioelectrical activity, these changes being uneven in various hypothalamic areas. Quantitative and qualitative differences of the changes were found in animals of different age. These changes of the hypothalamic bioelectrical activity seem to play an important role in the alterations of hemodynamic indices observed during chronic vasopressin administration.

Medial preoptic area and onset of maternal behavior in the rat.

The present series of experiments examined whether the medial preoptic area (MPOA) is involved in the onset of maternal behavior in the rat. Previously, the MPOA had been shown to be important in the maintenance of maternal behavior in the lactating rat. The first experiment investigated whether estradiol benzoate (EB) acts on the MPOA to facilitate the onset of maternal behavior in the 16-day pregnant, hysterectomized, and ovariectomized female rat. Such rats when given EB implants in the MPOA had significantly shorter latencies for the onset of maternal behavior than had females implanted with cholesterol in the MPOA or with EB in the ventromedial hypothalamus, in mammillary bodies, or under the skin. A second experiment showed that estrogen-induced prolactin release was not involved in this facilitation. A third experiment indicated that MPOA lesions disrupt the onset of maternal behavior that is induced by pup stimulation in virgin females. It was concluded that the MPOA is involved not only in the maintenance of maternal behavior but in the hormonally mediated onset of maternal behavior and the onset of maternal behavior induced in virgin females by pup stimulation.

Progesterone-sensitive loci for blockade of ovulation in the hamster.

PIP: Virgin female golden hamsters, 3-6 months old were implanted with progesterone, testosterone or cholesterol fused within the lumen of a hypodermic needle, or progesterone, cholesterol or paraffin fused into the end of a hypodermic tube or tungsten wire in order to determine progesterone-sensitive loci for blocking of ovulation. Molten steroid was drawn into 22-guage "thin wall", 27-guage 30-guage hypodermic tubing and then solidified. Large pellets (450 mcm) were made by dipping a 30-guage tube into molten steroid. Smaller pellets were made on the ends of tungsten wire (130 mcm). Pellets were measured on a shadowgraph to the nearest 10 mcm. The pellets were implanted through the top of the cranium and fastened with Kadon 22 dental cement. The implantation of 22-guage "thin wall" implants was performed 52-56 hours before ovulation and other implants 32-39 hours before the next expected ovulation. Hamsters were checked daily for ovulation by method of Orsini for 2 weeks after implantation. A hemi-ovarectomy and search for ova according to Reuter et al was performed on the day of their expected ovulation. The ovary was dissected and examined (10-30X magnification). The animals were sacrificed and brains removed, fixed in 10% formalin, serially sectioned at 100 mcm using a clinical freezing microtome, and stained with thronine to determine implantation site. Progesterone implants 18,000 sq. mcm larger resulted in blocking ovulation in the medial preoptic-diagonal band region of the hypothalamus. 28,000- 180,000 sq. mcm sizes also blocked ovulation when placed in the median eminence and in acurate nucleus regions of the hypothalamus but not in the hypophysis. The blocking effect of the hypophyseal implants can be explained by the lesion caused by the physical size of implants. Control substances did not block ovulation except when related to lesions caused by 450 mcm or 710 mcm diameter structures. Implants were effective in blocking ovulation for 2 weeks in larger implants and 1-3 days for smaller ones. The reason for this was not understood. Testosterone was also able to block ovulation in the medial preoptic-diagonal band region but to a significantly lesser degree than progesterone.^ieng