Electrophysiological Properties of the Medial Mammillary Bodies across the Sleep-Wake Cycle.

The medial mammillary bodies (MBs) play an important role in the formation of spatial memories; their dense inputs from hippocampal and brainstem regions makes them well placed to integrate movement-related and spatial information, which is then extended to the anterior thalamic nuclei and beyond to the cortex. While the anatomical connectivity of the medial MBs has been well studied, much less is known about their physiological properties, particularly in freely moving animals. We therefore carried out a comprehensive characterization of medial MB electrophysiology across arousal states by concurrently recording from the medial MB and the CA1 field of the hippocampus in male rats. In agreement with previous studies, we found medial MB neurons to have firing rates modulated by running speed and angular head velocity, as well as theta-entrained firing. We extended the characterization of MB neuron electrophysiology in three key ways: (1) we identified a subset of neurons (25%) that exhibit dominant bursting activity; (2) we showed that ∼30% of theta-entrained neurons exhibit robust theta cycle skipping, a firing characteristic that implicates them in a network for prospective coding of position; and (3) a considerable proportion of medial MB units showed sharp-wave ripple (SWR) responsive firing (∼37%). The functional heterogeneity of MB electrophysiology reinforces their role as an integrative node for mnemonic processing and identifies potential roles for the MBs in memory consolidation through propagation of SWR-responsive activity to the anterior thalamus and prospective coding in the form of theta cycle skipping.

Compromised mammillary body connectivity and psychotic symptoms in mice with di- and mesencephalic ablation of ST8SIA2.

Altered long-range connectivity is a common finding across neurodevelopmental psychiatric disorders, but causes and consequences are not well understood. Genetic variation in ST8SIA2 has been associated with schizophrenia, autism, and bipolar disorder, and St8sia2-/- mice show a number of related neurodevelopmental and behavioral phenotypes. In the present study, we use conditional knockout (cKO) to dissect neurodevelopmental defects and behavioral consequences of St8sia2 deficiency in cortical interneurons, their cortical environment, or in the di- and mesencephalon. Neither separate nor combined cortical and diencephalic ablation of St8sia2 caused the disturbed thalamus-cortex connectivity observed in St8sia2-/- mice. However, cortical ablation reproduced hypoplasia of corpus callosum and fornix and mice with di- and mesencephalic ablation displayed smaller mammillary bodies with a prominent loss of parvalbumin-positive projection neurons and size reductions of the mammillothalamic tract. In addition, the mammillotegmental tract and the mammillary peduncle, forming the reciprocal connections between mammillary bodies and Gudden's tegmental nuclei, as well as the size of Gudden's ventral tegmental nucleus were affected. Only mice with these mammillary deficits displayed enhanced MK-801-induced locomotor activity, exacerbated impairment of prepulse inhibition in response to apomorphine, and hypoanxiety in the elevated plus maze. We therefore propose that compromised mammillary body connectivity, independent from hippocampal input, leads to these psychotic-like responses of St8sia2-deficient mice.

Why Isn't the Head Direction System Necessary for Direction? Lessons From the Lateral Mammillary Nuclei.

Complex spatial representations in the hippocampal formation and related cortical areas require input from the head direction system. However, a recurrent finding is that behavior apparently supported by these spatial representations does not appear to require input from generative head direction regions, i.e., lateral mammillary nuclei (LMN). Spatial tasks that tax direction discrimination should be particularly sensitive to the loss of head direction information, however, this has been repeatedly shown not to be the case. A further dissociation between electrophysiological properties of the head direction system and behavior comes in the form of geometric-based navigation which is impaired following lesions to the head direction system, yet head direction cells are not normally guided by geometric cues. We explore this apparent mismatch between behavioral and electrophysiological studies and highlight future experiments that are needed to generate models that encompass both neurophysiological and behavioral findings.

Lesions to the lateral mammillary nuclei disrupt spatial learning in rats.

The head direction (HD) signal is thought to originate in the reciprocal connections between the dorsal tegmental nuclei (DTN) and the lateral mammillary nuclei (LMN) and lesions to these structures disrupt the HD signal in downstream structures. Lesions to the DTN also disrupt performance on spatial tasks where directional heading is thought to be important. In Experiment 1, rats with bilateral electrolytic lesions of the LMN and sham controls were trained on 2 tasks previously shown to be sensitive to DTN damage. Rats were first trained on either a direction or rotation problem in a water T maze. LMN-lesioned rats were impaired relative to sham controls, on both the first block of 8 trials and on the total number of trials taken to reach criterion. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in a food cup at the center of the table, and return to the home cage. Again, LMN-lesioned rats were impaired relative to sham rats, making more errors on the return component of the foraging trip. In Experiment 2, rats with electrolytic LMN lesions were also impaired on a dry land version of the direction and rotation problems and had difficulty discriminating between reinforced and nonreinforced locations on a 12-arm maze. These results build on previous behavioral and cell-recording studies and demonstrate the importance of the direction system to spatial learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Mammillary body regulates state-dependent fear by alternating cortical oscillations.

State-dependent memory describes a phenomenon that memory will be efficiently retrieved only when the brain state during retrieval matches the state during encoding. While a variety of psychoactive drugs, such as ethanol, cocaine, morphine and NMDA receptor antagonists, are able to induce state-dependent memory, the biological hallmark of brain state and neural mechanism of its regulation are still unknown. In this study, we found that MK-801 enhanced delta oscillations in awake mice, representing a drug-induced brain state, in which fear memory could only be successfully retrieved when the same drug condition was presented. We identified a key nucleus, mammillary body (MB), which regulates the specific brain state associated with MK-801. Chemogenetic silencing of MB neurons enhanced cortical delta oscillations and generated state-dependent memory. Moreover, optogenetic reconstitution of delta oscillations alone facilitated retrieval of fear memory encoded under MK-801. Our results indicated that delta oscillations in awake animals defined a specific brain state, in which memory formed is inaccessible under the normal condition, shining light on the neural mechanism underlying the fluctuation of memory retrieval and the role of MB in memory encoding and recall.

Mammillothalamic and Mammillotegmental Tracts as New Targets for Dementia and Epilepsy Treatment.

BACKGROUND: Recently, neuromodulation through deep brain stimulation (DBS) has appeared as a new surgical procedure in the treatment of some types of dementia and epilepsy. The mammillothalamic and mammillotegmental tracts are involved among the new targets. To our knowledge, a review article focused specifically on these mammillary body efferents is lacking in the medical literature. Their contribution to memory is, regrettably, often overlooked. METHODS: A review of the relevant literature was conducted. RESULTS: There is evidence that mammillary bodies can contribute to memory independently from hippocampal formation, but the mechanism is not yet known. Recent studies in animals have provided evidence for the specific roles of these mammillary body efferents in regulating memory independently. In animal studies, it has been shown that the disruption of the mammillothalamic tract inhibits seizures and that electrical stimulation of the mammillary body or mammillothalamic tract raises the seizure threshold. In humans, DBS targeting the mammillary body through the mammillothalamic tract or the stimulation of the anterior thalamic nucleus, especially in the areas closely related to the mammillothalamic tract, has been found effective in patients with medically refractory epilepsy. Nonetheless, little knowledge exists on the functional anatomy of the mammillary body efferents, and their role in the exact mechanism of epileptogenic activity and in the memory function of the human brain. CONCLUSIONS: A comprehensive knowledge of the white matter anatomy of the mammillothalamic and mammillotegmental tracts is crucial since they have emerged as new DBS targets in the treatment of various disorders including dementia and epilepsy.

Bi-Directional Theta Modulation between the Septo-Hippocampal System and the Mammillary Area in Free-Moving Rats.

Hippocampal (HPC) theta oscillations have long been linked to various functions of the brain. Many cortical and subcortical areas that also exhibit theta oscillations have been linked to functional circuits with the hippocampus on the basis of coupled activities at theta frequencies. We examine, in freely moving rats, the characteristics of diencephalic theta local field potentials (LFPs) recorded in the supramammillary/mammillary (SuM/MM) areas that are bi-directionally connected to the HPC through the septal complex. Using partial directed coherence (PDC), we find support for previous suggestions that SuM modulates HPC theta at higher frequencies. We find weak separation of SuM and MM by dominant theta frequency recorded locally. Contrary to oscillatory cell activities under anesthesia where SuM is insensitive, but MM is sensitive to medial septal (MS) inactivation, theta LFPs persisted and became indistinguishable after MS-inactivation. However, MS-inactivation attenuated SuM/MM theta power, while increasing the frequency of SuM/MM theta. MS-inactivation also reduced root mean squared power in both HPC and SuM/MM equally, but reduced theta power differentially in the time domain. We provide converging evidence that SuM is preferentially involved in coding HPC theta at higher frequencies, and that the MS-HPC circuit normally imposes a frequency-limiting modulation over the SuM/MM area as suggested by cell-based recordings in anesthetized animals. In addition, we provide evidence that the postulated SuM-MS-HPC-MM circuit is under complex bi-directional control, rather than SuM and MM having roles as unidirectional relays in the network.

The effect of pharmacological inactivation of the mammillary body and anterior thalamic nuclei on hippocampal theta rhythm in urethane-anesthetized rats.

The mammillary body (MB) and the anterior thalamic nuclei (ATN) are closely related structures, which take part in learning and memory processes. However, the exact role of these structures has remained unclear. In both structures neurons firing according to hippocampal theta rhythm have been found, mainly in the medial mammillary nucleus (MM) and anteroventral thalamic nucleus (AV). These neurons are driven by descending projections from the hippocampal formation and are thought to convey theta rhythm back to the hippocampus (HP). We argue that the MB-ATN axis not only relays theta signal, but may also modulate it. To examine it, we performed a pharmacological inactivation of the MM and AV by local infusion of procaine, and measured changes in theta activity in selected structures of the extended hippocampal system in urethane-anesthetized rats. The inactivation of the MM resulted in decrease in EEG power in the HP and AV, the most evidently in the lower theta frequency bands, i.e. 3-5Hz in the HP (down to 9.2% in 3- to 4-Hz band and 37.6% in 4- to 5-Hz band, in comparison to the power in the control conditions) and 3-4Hz in the AV (down to 24.9%). After the AV inactivation, hippocampal EEG power decreased in theta frequency bands of 3-8Hz (down to 61.6% in 6- to 7-Hz band and 69.4% in 7- to 8-Hz band). Our results suggest that the role of the MB-ATN axis in regulating theta rhythm signaling may be much more important than has been speculated so far.

Induction of Lactation in the Biological Mother After Gestational Surrogacy of Twins: A Novel Approach and Review of Literature.

One of the important challenges in surrogate pregnancies is the early bonding of genetic mother with her infant and the establishment of breastfeeding. A combination of pharmacological and nonpharmacological methods is often used for the induction of lactation. Reports of induced lactation in surrogacy are limited and scattered. In this report, we present a case of induced lactation and initiation of breastfeeding in preterm twins by the genetic mother, through her novel approach after a gestational surrogate pregnancy. Thematic approach of maternal account is summarized with context and rigor. We reviewed the reported literature of induced lactation in similar cases with an aim to address the various methods adopted.

Serotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat.

Theta activity has been related to the processing of spatial information and the formation of hippocampus-dependent memory. The medial septum (MS) plays an important role in the control and coordination of theta activity, as well as in the modulation of learning. It has been established that increased serotonergic activity may desynchronize theta activity, while reduced serotonergic activity produces continuous and persistent theta activity in the hippocampus. We investigate whether serotonin acting on the medial septum could modify spatial learning and the functional relationship between septo-hippocampal and septo-mammillary theta activity. The serotonin was depleted (5HT-D) from the medial septum by the injection of 5,7 DHT (5,7- dihydroxytryptamine). Theta activity was recorded in the dorsal hippocampus, MS and mammillary nuclei (SUM, MM) of Sprague-Dawley male rats during spatial learning in the Morris water maze. Spatial learning was facilitated, and the frequency of the hippocampal theta activity during the first days of training increased (to 8.5Hz) in the 5HT-D group, unlike the vehicle group. Additionally, the coherence between the MS-hippocampus and the MS-mammillary nuclei was higher during the second day of the test compared to the vehicle group. We demonstrated that septal serotonin depletion facilitates the acquisition of spatial information in association with a higher functional coupling of the medial septum with the hippocampus and mammillary nuclei. Serotonin, acting in the medial septum, modulates hippocampal theta activity and spatial learning.

The head direction cell system and behavior: The effects of lesions to the lateral mammillary bodies on spatial memory in a novel landmark task and in the water maze.

The head direction system is composed of neurons found in a number of connected brain areas that fire in a sharply tuned, directional way. The function of this system, however, has not been fully established. To assess this, we devised a novel spatial landmark task, comparable to the paradigms in which stimulus control has been assessed for spatially tuned neurons. The task took place in a large cylinder and required rats to dig in a specific sand cup, from among 16 alternatives, to obtain a food reward. The reinforced cup was in a fixed location relative to a salient landmark, and probe sessions confirmed that the landmark exerted stimulus control over the rats' cup choices. To assess the contribution of the head direction cell system to this memory task, half of the animals received ibotenic acid infusions into the lateral mammillary nuclei (LMN), an essential node in the head direction network, while the other received sham lesions. No differences were observed in performance of this task between the 2 groups. Animals with LMN lesions were impaired, however, in reversal learning on a water maze task. These results suggest that the LMN, and potentially the head direction cell system, are not essential for the use of visual landmarks to guide spatial behavior.

The mammillary bodies and memory: more than a hippocampal relay.

Although the mammillary bodies were one of the first neural structures to be implicated in memory, it has long been assumed that their main function was to act primarily as a hippocampal relay, passing information on to the anterior thalamic nuclei and from there to the cingulate cortex. This view not only afforded the mammillary bodies no independent role in memory, it also neglected the potential significance of other, nonhippocampal, inputs to the mammillary bodies. Recent advances have transformed the picture, revealing that projections from the tegmental nuclei of Gudden, and not the hippocampal formation, are critical for sustaining mammillary body function. By uncovering a role for the mammillary bodies that is independent of its subicular inputs, this work signals the need to consider a wider network of structures that form the neural bases of episodic memory.

Visualization of Pulsatile CSF Motion Around Membrane-like Structures with both 4D Velocity Mapping and Time-SLIP Technique.

PURPOSE: We compared the depiction of pulsatile CSF motion obtained by 4-dimensional phase-contrast velocity mapping (4D-VM) with that by time-spatial labeling inversion pulse (time-SLIP) technique in the presence of membrane structures. MATERIALS AND METHODS: We compared the 2 techniques using a flow phantom comprising tubes with and without a thin rubber membrane and applied the techniques to 6 healthy volunteers and 2 patients to analyze CSF dynamics surrounding thin membrane structures, such as the Liliequist membrane (LM), or the wall of an arachnoid cyst. RESULTS: Phantom images exhibited propagation of the flow and pressure gradient beyond the membrane in the tube. In contrast, fluid labeled by the time-SLIP technique showed little displacement from the blockage of spin travelling by the membrane. A similar phenomenon was observed around the LM in healthy volunteers and the arachnoid cyst wall in a patient. CONCLUSION: Four-dimensional phase-contrast velocity mapping permitted visualization of the propagation of CSF pulsation through the intracranial membranous structures. This suggests that 4D-VM and the time-SLIP technique provide different information on flow and that both techniques are useful for classifying the pathophysiological status of CSF and elucidating the propagation pathway of CSF pulsation in the cranium.

The importance of the context in the hippocampus and brain related areas throughout the performance of a fear conditioning task.

The importance context has been broadly studied in the management of phobias and in the drug addiction literature. The way in which changes to a context influence behavior after the simple acquisition of a passive avoidance task remains unclear. The hippocampus has long been implicated in the contextual and spatial processing required for contextual fear, but its role in encoding the aversive component of a contextual fear memory is still inconclusive. Our work tries to elucidate whether a change in context, represented as differences in the load of the stimuli, is critical for learning about the context-shock association and whether this manipulation of the context could be linked to any change in metabolic brain activity requirements. For this purpose, we used an avoidance conditioning task. Animals were divided into three different experimental conditions. In one group, acquisition was performed in an enriched stimuli environment and retention was performed in a typically lit chamber (the PA-ACQ-CONTX group). In another group, acquisition was performed in the typically lit chamber and retention was undertaken in the highly enriched chamber (the PA-RET-CONTX group). Finally, for the control group, PA-CN-CONTX, acquisition, and retention were performed in the enriched stimuli environment. Our results showed that the PA-ACQ-CONTX group had longer escape latencies and poorer retention than the PA-RET-CONTX and PA-CN-CONTX groups after 24 h of acquisition under contextual changes. To study metabolic brain activity, histochemical labelling of cytochrome c-oxidase (CO) was performed. CO results suggested a neural circuit including the hippocampus, amygdala, thalamus, parahippocampal cortices, and mammillary nuclei that is involved in the learning and memory processes that enable context-dependent behavior. These results highlight how dysfunction in this network may be involved in the contextualization of fear associations that underlie several forms of psychopathology, including post-traumatic stress disorder, schizophrenia, and substance abuse disorders.

Visual landmark information gains control of the head direction signal at the lateral mammillary nuclei.

The neural representation of directional heading is conveyed by head direction (HD) cells located in an ascending circuit that includes projections from the lateral mammillary nuclei (LMN) to the anterodorsal thalamus (ADN) to the postsubiculum (PoS). The PoS provides return projections to LMN and ADN and is responsible for the landmark control of HD cells in ADN. However, the functional role of the PoS projection to LMN has not been tested. The present study recorded HD cells from LMN after bilateral PoS lesions to determine whether the PoS provides landmark control to LMN HD cells. After the lesion and implantation of electrodes, HD cell activity was recorded while rats navigated within a cylindrical arena containing a single visual landmark or while they navigated between familiar and novel arenas of a dual-chamber apparatus. PoS lesions disrupted the landmark control of HD cells and also disrupted the stability of the preferred firing direction of the cells in darkness. Furthermore, PoS lesions impaired the stable HD cell representation maintained by path integration mechanisms when the rat walked between familiar and novel arenas. These results suggest that visual information first gains control of the HD cell signal in the LMN, presumably via the direct PoS → LMN projection. This visual landmark information then controls HD cells throughout the HD cell circuit.

How do mammillary body inputs contribute to anterior thalamic function?

It has long been assumed that the main function of the mammillary bodies is to provide a relay for indirect hippocampal inputs to the anterior thalamic nuclei. Such models afford the mammillary bodies no independent role in memory and overlook the importance of their other, non-hippocampal, inputs. This review focuses on recent advances that herald a new understanding of the importance of the mammillary bodies, and their inputs from the limbic midbrain, for anterior thalamic function. It has become apparent that the mammillary bodies' contribution to memory is not dependent on afferents from the subicular complex. Rather, the ventral tegmental nucleus of Gudden is a vital source of inputs that support memory processes within the medial mammillary bodies. In parallel, the lateral mammillary bodies, via their connections with the dorsal tegmental nucleus of Gudden, are critical for generating head-direction signals. These two parallel, but distinct, information streams converge on the anterior thalamic nuclei and support different aspects of spatial memory.

Mammilliothalamic tract lesions disrupt tests of visuo-spatial memory.

The mammillary bodies and their projections via the mammilliothalamic tract to the anterior thalamic nuclei are known to be important for spatial memory in rodents, but their precise role remains unclear. To determine whether transection of the mammilliothalamic tract can produce deficits on tests of spatial memory even when the navigational demands placed on the animal are limited, rats with discrete mammilliothalamic tract lesions were tested on the ability to use distal visual cues to discriminate between 2 locations within a room, irrespective of the direction traveled (Experiment 1). Animals with mammilliothalamic tract lesions acquired this task more slowly and less accurately than control animals. Consistent with this impairment in discriminating different spatial locations, the same lesions also severely disrupted object-in-place memory but spared performance on standard tests of object recognition memory (Experiment 2). Finally, to compare performance on a task that is known to be sensitive to mammilliothalamic transection and requires animals to actively navigate within their environment, the effect of the lesions on spatial working memory in the radial-arm maze was examined. Taken together, the results suggest that even when there are little or no navigational demands, mammilliothalamic tract damage still results in impoverished encoding of spatial location.

The habenulo-interpeduncular and mammillothalamic tracts: early developed fiber tracts in the human fetal diencephalon.

PURPOSE: The habenulo-interpeduncular (HI) and mammillothalamic (MT) tracts are phylogenetically ancient. The clinical relevance of these tracts has recently received attention. In this work, we map the anatomy the developing HI and MT. METHODS: To investigate the topographical anatomy of developing fiber tracts in and around the diencephalon, we examined the horizontal, frontal, and sagittal serial paraffin sections of 28 human fetuses at 8-12 weeks of gestation. RESULTS: In all specimens, eosinophilic early fiber bundles were limited to the bilateral HI and MT tracts in contrast to pale-colored later developing fibers such as the thalamocortical projections and optic tract. The HI and MT tracts ran nearly parallel and sandwiched the thalamus from the dorsal and ventral sides, respectively. The nerve tract course appeared to range from 5-7 mm for the HI tract and 3-5 mm for the MT tract in 15 specimens at 11-12 weeks. The HI tract was embedded in, adjacent to, or distant from the developing parvocellular red nucleus. CONCLUSIONS: In early human fetuses, HI and MT tracts might be limited pathways for primitive cholinergic fiber connections between the ventral midbrain and epithalamic limbic system.

Spatial memory extinction: a c-Fos protein mapping study.

While the neuronal basis of spatial memory consolidation has been thoroughly studied, the substrates mediating the process of extinction remain largely unknown. This study aimed to evaluate the functional contribution of selected brain regions during the extinction of a previously acquired spatial memory task in the Morris water maze. For that purpose, we used adult male Wistar rats trained in a spatial reference memory task. Learning-related changes in c-Fos inmunoreactive cells after training were evaluated in cortical and subcortical regions. Results show that removal of the hidden platform in the water maze induced extinction of the previously reinforced escape behavior after 16 trials, without spontaneous recovery 24h later. Extinction was related with significantly higher numbers of c-Fos positive nuclei in amygdala nuclei and prefrontal cortex. On the other hand, the lateral mammillary bodies showed higher number of c-Fos positive cells than the control group. Therefore, in contrast with the results obtained in studies of classical conditioning, we show the involvement of diencephalic structures mediating this kind of learning. In summary, our findings suggest that medial prefrontal cortex, the amygdala complex and diencephalic structures like the lateral mammillary nuclei are relevant for the extinction of spatial memory.

Day-night differences in neural activation in histaminergic and serotonergic areas with putative projections to the cerebrospinal fluid in a diurnal brain.

In nocturnal rodents, brain areas that promote wakefulness have a circadian pattern of neural activation that mirrors the sleep/wake cycle, with more neural activation during the active phase than during the rest phase. To investigate whether differences in temporal patterns of neural activity in wake-promoting regions contribute to differences in daily patterns of wakefulness between nocturnal and diurnal species, we assessed Fos expression patterns in the tuberomammillary (TMM), supramammillary (SUM), and raphe nuclei of male grass rats maintained in a 12:12 h light-dark cycle. Day-night profiles of Fos expression were observed in the ventral and dorsal TMM, in the SUM, and in specific subpopulations of the raphe, including serotonergic cells, with higher Fos expression during the day than during the night. Next, to explore whether the cerebrospinal fluid is an avenue used by the TMM and raphe in the regulation of target areas, we injected the retrograde tracer cholera toxin subunit beta (CTB) into the ventricular system of male grass rats. While CTB labeling was scarce in the TMM and other hypothalamic areas including the suprachiasmatic nucleus, which contains the main circadian pacemaker, a dense cluster of CTB-positive neurons was evident in the caudal dorsal raphe, and the majority of these neurons appeared to be serotonergic. Since these findings are in agreement with reports for nocturnal rodents, our results suggest that the evolution of diurnality did not involve a change in the overall distribution of neuronal connections between systems that support wakefulness and their target areas, but produced a complete temporal reversal in the functioning of those systems.