Basal Forebrain Impairment: Understanding the Mnemonic Function of the Septal Region Translates in Therapeutic Advances.

The basal forebrain is one of the three major brain circuits involved in episodic memory formation together with the hippocampus and the diencephalon. The dysfunction of each of these regions is known to cause anterograde amnesia. While the hippocampal pyramidal neurons are known to encode episodic information and the diencephalic structures are known to provide idiothetic information, the contribution of the basal forebrain to memory formation has been exclusively associated with septo-hippocampal cholinergic signaling. Research data from the last decade broadened our understanding about the role of septal region in memory formation. Animal studies revealed that septal neurons process locomotor, rewarding and attentional stimuli. The integration of these signals results in a systems model for the mnemonic function of the medial septum that could guide new therapeutic strategies for basal forebrain impairment (BFI). BFI includes the disorders characterized with basal forebrain amnesia and neurodegenerative disorders that affect the basal forebrain. Here, we demonstrate how the updated model of septal mnemonic function can lead to innovative translational treatment approaches that include pharmacological, instrumental and behavioral techniques.

Neurons under genetic control: What are the next steps towards the treatment of movement disorders?

Since the implementation of deep-brain stimulation as a therapy for movement disorders, there has been little progress in the clinical application of novel alternative treatments. Movement disorders are a group of neurological conditions, which are characterised with impairment of voluntary movement and share similar anatomical loci across the basal ganglia. The focus of the current review is on Parkinson's disease and Huntington's disease as they are the most investigated hypokinetic and hyperkinetic movement disorders, respectively. The last decade has seen enormous advances in the development of laboratory techniques that control neuronal activity. The two major ways to genetically control the neuronal function are: 1) expression of light-sensitive proteins that allow for the optogenetic control of the neuronal spiking and 2) expression or suppression of genes that control the transcription and translation of proteins. However, the translation of these methodologies from the laboratories into the clinics still faces significant challenges. The article summarizes the latest developments in optogenetics and gene therapy. Here, I compare the physiological mechanisms of established electrical deep brain stimulation to the experimental optogenetical deep brain stimulation. I compare also the advantages of DNA- and RNA-based techniques for gene therapy of familial movement disorders. I highlight the benefits and the major issues of each technique and I discuss the translational potential and clinical feasibility of optogenetic stimulation and gene expression control. The review emphasises recent technical breakthroughs that could initiate a notable leap in the treatment of movement disorders.

Extrafield Activity Shifts the Place Field Center of Mass to Encode Aversive Experience.

Hippocampal place cells are known to have a key role in encoding spatial information. Aversive stimuli, such as predator odor, evoke place field remapping and a change in preferred firing locations. However, it remains unclear how place cells use positive or negative experiences to remap. We investigated whether CA1 place cells, recorded from behaving rats, remap randomly or whether their reconfiguration depends on the perceived location of the aversive stimulus. Exposure to trimethylthiazoline (TMT; an innately aversive odor), increased the amplitude of hippocampal ß oscillations in the two arms of the maze in which TMT exposure occurred. We found that a population of place cells with fields located outside the TMT arms increased their activity (extrafield spiking) in the TMT arms during the aversive episodes. Moreover, in the subsequent post-TMT recording, these cells exhibited a significant shift in their center of mass (COM) towards the TMT arms. The induction of extrafield plasticity was mediated by the basolateral amygdala complex (BLA). Photostimulation of the BLA triggered aversive behavior, synchronized hippocampal local field oscillations, and increased the extrafield spiking of the hippocampal place cells for the first 100 ms after light delivery. Optogenetic BLA activation triggered an increase in extrafield spiking activity that was correlated with the degree of place field plasticity. Furthermore, BLA-mediated increase of the extrafield activity predicts the degree of subsequent field plasticity. Our findings demonstrate that that the remapping of hippocampal place cells during aversive episodes is not random but it depends on the location of the aversive stimulus.

Differential response of hippocampal and prefrontal oscillations to systemic LPS application.

The early electrophysiological phenomena linked to systemic inflammation are largely underexplored. We developed here local field analyses to detect prodromal oscillatory abnormalities. We identified early band-specific patterns in local field potential recorded from freely-moving rats injected intraperitoneally with lipopolysaccharide (LPS, 1 mg/kg). Theta frequency was significantly reduced and this effect was not related to the decreased locomotion of the animal. Furthermore, LPS-induced alterations show a region-specific response when compared between the hippocampal region and medial prefrontal cortex. Delta mean frequency increased in the hippocampal region but not in the prefrontal cortex. We explored also the hypothesis that systemic inflammation increases the propensity of abnormally synchronized brain activity. Our data indicate that the LPS-evoked alteration of delta and theta frequency parameters reflects the formation of abnormal synchronization in similar frequency ranges. The onset of abnormal brain activity was indicated by spike-wave discharges in the range of 1-10 Hz with three main frequency domains. Importantly, the occurrence of spike-wave discharges was observed in the hippocampus but not in the cortex. In summary, the hippocampal theta rhythm is an accurate indicator of the oscillatory changes evoked by LPS application. The findings offer clear patterns of altered brain function that will facilitate mechanistic investigations of brain dysfunction and delirium occurring during sepsis.

Differential and complementary roles of medial and lateral septum in the orchestration of limbic oscillations and signal integration.

Anatomical differences between the medial and lateral septum have associated these nuclei with dissimilar functional roles and behaviours. While the medial septum has been implicated, predominantly, in theta rhythm generation along the septo-hippocampal axis, the lateral septum has mainly been investigated in the context of septo-hypothalamic dialogue. Recent advances suggest that medial and lateral septum are more closely functionally related than previously appreciated. Here, we explore the hypothesis that the medial septum mediates ascending septo-hippocampal theta propagation, while the lateral septum processes a descending hippocampo-septal and septo-hypothalamic reinforcement signal that mediates navigation during motivated behaviour. The generation and propagation of theta rhythm are critical for the initiation of exploratory behaviour. Indeed, theta signal processing of medial and lateral septum nuclei may well be involved in the integration of spatial, rewarding and locomotor signals across different brain networks. We review here the structural features, anatomical connectivity and functional properties of the medial and lateral septum. We discuss the heterogeneous anatomy of the lateral septum, which is composed of diverse subregions with distinct ascending and descending projections, and we relate the physiological characteristics of septal nuclei to their functional relationships with the hippocampal formation, the hypothalamus and the brainstem reticular formation during motivated spatial navigation.

Speed and Oscillations: Medial Septum Integration of Attention and Navigation.

Several cortical and diencephalic limbic brain regions incorporate neurons that fire in correlation with the speed of whole-body motion, also known as linear velocity. Besides the field mapping and head-directional information, the linear velocity is among the major signals that guide animal's spatial navigation. Large neuronal populations in the same limbic regions oscillate with theta rhythm during spatial navigation or attention episodes; and the frequency of theta also correlates with linear velocity. A functional similarity between these brain areas is that their inactivation impairs the ability to form new spatial memories; whereas an anatomical similarity is that they all receive projections from medial septum-diagonal band of Broca complex. We review recent findings supporting the model that septal theta rhythm integrates different sensorimotor signals necessary for spatial navigation. The medial septal is described here as a circuitry that mediates experience-dependent balance of sustained attention and path integration during navigation. We discuss the hypothesis that theta rhythm serves as a key mechanism for the aligning of intrinsic spatial representation to: (1) rapid change of position in the spatial environment; (2) continuous alteration of sensory signals throughout navigation; and (3) adapting levels of attentional behavior. The synchronization of these spatial, somatosensory and neuromodulatory signals is proposed here to be anatomically and physiologically mediated by the medial septum.

Place field assembly distribution encodes preferred locations.

The hippocampus is the main locus of episodic memory formation and the neurons there encode the spatial map of the environment. Hippocampal place cells represent location, but their role in the learning of preferential location remains unclear. The hippocampus may encode locations independently from the stimuli and events that are associated with these locations. We have discovered a unique population code for the experience-dependent value of the context. The degree of reward-driven navigation preference highly correlates with the spatial distribution of the place fields recorded in the CA1 region of the hippocampus. We show place field clustering towards rewarded locations. Optogenetic manipulation of the ventral tegmental area demonstrates that the experience-dependent place field assembly distribution is directed by tegmental dopaminergic activity. The ability of the place cells to remap parallels the acquisition of reward context. Our findings present key evidence that the hippocampal neurons are not merely mapping the static environment but also store the concurrent context reward value, enabling episodic memory for past experience to support future adaptive behavior.

Medial septum regulates the hippocampal spatial representation.

The hippocampal circuitry undergoes attentional modulation by the cholinergic medial septum. However, it is unclear how septal activation regulates the spatial properties of hippocampal neurons. We investigated here what is the functional effect of selective-cholinergic and non-selective septal stimulation on septo-hippocampal system. We show for the first time selective activation of cholinergic cells and their differential network effect in medial septum of freely-behaving transgenic rats. Our data show that depolarization of cholinergic septal neurons evokes frequency-dependent response from the non-cholinergic septal neurons and hippocampal interneurons. Our findings provide vital evidence that cholinergic effect on septo-hippocampal axis is behavior-dependent. During the active behavioral state the activation of septal cholinergic projections is insufficient to evoke significant change in the spiking of the hippocampal neurons. The efficiency of septo-hippocampal processing during active exploration relates to the firing patterns of the non-cholinergic theta-bursting cells. Non-selective septal theta-burst stimulation resets the spiking of hippocampal theta cells, increases theta synchronization, entrains the spiking of hippocampal place cells, and tunes the spatial properties in a timing-dependent manner. The spatial properties are augmented only when the stimulation is applied in the periphery of the place field or 400-650 ms before the animals approached the center of the field. In summary, our data show that selective cholinergic activation triggers a robust network effect in the septo-hippocampal system during inactive behavioral state, whereas the non-cholinergic septal activation regulates hippocampal functional properties during explorative behavior. Together, our findings uncover fast septal modulation on hippocampal network and reveal how septal inputs up-regulate and down-regulate the encoding of spatial representation.

Septo-hippocampal signal processing: breaking the code.

The septo-hippocampal connections appear to be a key element in the neuromodulatory cholinergic control of the hippocampal neurons. The cholinergic neuromodulation is well established in shifting behavioral states of the brain. The pacemaker role of medial septum in the limbic theta rhythm is demonstrated by lesions and pharmacological manipulations of GABAergic neurons, yet the link between the activity of different septal neuronal classes and limbic theta rhythm is not fully understood. We know even less about the information transfer between the medial septum and hippocampus--is there a particular kind of processed information that septo-hippocampal pathways transmit? This review encompasses fundamental findings together with the latest data of septo-hippocampal signal processing to tackle the frontiers of our understanding about the functional significance of medial septum to the hippocampal formation.

Decoding signal processing in thalamo-hippocampal circuitry: implications for theories of memory and spatial processing.

A major tool in understanding how information is processed in the brain is the analysis of neuronal output at each hierarchical level through which neurophysiological signals are propagated. Since the experimental brain operation performed on Henry Gustav Molaison (known as patient H.M.) in 1953, the hippocampal formation has gained special attention, resulting in a very large number of studies investigating signals processed by the hippocampal formation. One of the main information streams to the hippocampal formation, vital for episodic memory formation, arises from thalamo-hippocampal projections, as there is extensive connectivity between these structures. This connectivity is sometimes overlooked by theories of memory formation by the brain, in favour of theories with a strong cortico-hippocampal flavour. In this review, we attempt to address some of the complexity of the signals processed within the thalamo-hippocampal circuitry. To understand the signals encoded by the anterior thalamic nuclei in particular, we review key findings from electrophysiological, anatomical, behavioural and computational studies. We include recent findings elucidating the integration of different signal modalities by single thalamic neurons; we focus in particular on the propagation of two prominent signals: head directionality and theta rhythm. We conclude that thalamo-hippocampal processing provides a centrally important, substantive, and dynamic input modulating and moderating hippocampal spatial and mnemonic processing. This article is part of a Special Issue entitled SI: Brain and Memory.

The irregular firing properties of thalamic head direction cells mediate turn-specific modulation of the directional tuning curve.

Head direction cells encode an animal's heading in the horizontal plane. However, it is not clear why the directionality of a cell's mean firing rate differs for clockwise, compared with counterclockwise, head turns (this difference is known as the "separation angle") in anterior thalamus. Here we investigated in freely behaving rats whether intrinsic neuronal firing properties are linked to this phenomenon. We found a positive correlation between the separation angle and the spiking variability of thalamic head direction cells. To test whether this link is driven by hyperpolarization-inducing currents, we investigated the effect of thalamic reticular inhibition during high-voltage spindles on directional spiking. While the selective directional firing of thalamic neurons was preserved, we found no evidence for entrainment of thalamic head direction cells by high-voltage spindle oscillations. We then examined the role of depolarization-inducing currents in the formation of separation angle. Using a single-compartment Hodgkin-Huxley model, we show that modeled neurons fire with higher frequencies during the ascending phase of sinusoidal current injection (mimicking the head direction tuning curve) when simulated with higher high-threshold calcium channel conductance. These findings demonstrate that the turn-specific encoding of directional signal strongly depends on the ability of thalamic neurons to fire irregularly in response to sinusoidal excitatory activation. Another crucial factor for inducing phase lead to sinusoidal current injection was the presence of spike-frequency adaptation current in the modeled neurons. Our data support a model in which intrinsic biophysical properties of thalamic neurons mediate the physiological encoding of directional information.

Respiratory cycle entrainment of septal neurons mediates the fast coupling of sniffing rate and hippocampal theta rhythm.

Memory for odour information may result from temporal coupling between the olfactory and hippocampal systems. Respiration defines the frequency of olfactory perception, but how the respiratory rate affects hippocampal oscillations remains poorly understood. The afferent connectivity of the medial septum/diagonal band of Broca complex (MS/DB) proposes this region as a crossroads between respiratory and limbic pathways. Here we investigate if the firing rates of septal neurons integrate respiratory rate signals. We demonstrate that approximately 50% of MS/DB neurons are temporally correlated with sniffing frequency. Moreover, a group of slow-spiking septal neurons are phase-locked to the sniffing cycle. We show that inter-burst intervals of MS/DB theta cells relate to the sniff rate. Intranasal odour infusion evokes sniff phase preference for the activity of fast-spiking MS/DB neurons. Concurrently, the infusion augments the correlation between sniffing and limbic theta oscillations. During periods of sniffing-theta correlation, CA1 place cells fired preferentially during the inhalation phase, suggesting the theta cycle as a coherent time frame for central olfactory processing. Furthermore, injection of the GABAergic agonist muscimol into medial septum induces a parallel decrease of sniffing and theta frequencies. Our findings provide experimental evidence that MS/DB does not merely generate theta rhythm, but actively integrates sensorimotor stimuli that reflect sniffing rate. Such integration may provide temporal oscillatory synchronisation of MS/DB-innervated limbic structures with the sniffing cycle.

The anterior thalamus provides a subcortical circuit supporting memory and spatial navigation.

The anterior thalamic nuclei (ATN), a central component of Papez' circuit, are generally assumed to be key constituents of the neural circuits responsible for certain categories of learning and memory. Supporting evidence for this contention is that damage to either of two brain regions, the medial temporal lobe and the medial diencephalon, is most consistently associated with anterograde amnesia. Within these respective regions, the hippocampal formation and the ATN (anteromedial, anteroventral, and anterodorsal) are the particular structures of interest. The extensive direct and indirect hippocampal-anterior thalamic interconnections and the presence of theta-modulated cells in both sites further support the hypothesis that these structures constitute a neuronal network crucial for memory and cognition. The major tool in understanding how the brain processes information is the analysis of neuronal output at each hierarchical level along the pathway of signal propagation coupled with neuroanatomical studies. Here, we discuss the electrophysiological properties of cells in the ATN with an emphasis on their role in spatial navigation. In addition, we describe neuroanatomical and functional relationships between the ATN and hippocampal formation.

Rosiglitazone enhances learning, place cell activity, and synaptic plasticity in middle-aged rats.

As an antidiabetic agent, rosiglitazone (ROSI) binds and activates peroxisome proliferator-activator receptor gamma (PPARγ), altering the expression of genes involved in glucose uptake and disposal, ultimately affecting glucose regulation. ROSI might therefore be a potential treatment to ameliorate age-related decline in cognitive function, particularly on an insulin-resistant background, where improvements in peripheral insulin sensitivity and central nervous system (CNS) glucose utilization may facilitate recovery of cognitive function. We therefore examined the amelioration potential of ROSI for neurocognitive deficits resulting from aging in an animal model. Behaviorally, acute and chronic ROSI treatments enhanced acquisition of learning in the water plus maze, a modified version of the Morris water maze task. In parallel, restoration of synaptic plasticity in the dentate gyrus of ROSI-treated middle-aged rats was evident after a single dose intake. Additionally, the spatial receptive fields of hippocampal CA1 place cells were significantly improved by chronic ROSI administration. ROSI treatment reversed basal plasma insulin abnormalities and increased hippocampal glucose transporter (GLUT)-3 expression in middle-aged rats. Taken together, these results suggest that ROSI modulates hippocampal circuitry effectively to promote an improvement in cognitive function, possibly via a glucose transporter-3 mechanism.

Theta-modulated head direction cells in the rat anterior thalamus.

A major tool in understanding how the brain processes information is the analysis of neuronal output at each hierarchical level along the pathway of signal propagation. Theta rhythm and head directionality are the two main signals found across all levels of Papez's circuit, which supports episodic memory formation. Here, we provide evidence that the functional interaction between both signals occurs at a subcortical level. We show that there is population of head direction cells (39%) in rat anteroventral thalamic nucleus that exhibit rhythmic spiking in the theta range. This class of units, termed HD-by-theta (head direction-by-theta) cells, discharged predominantly in spike trains at theta frequency (6-12 Hz). The highest degree of theta rhythmicity was evident when the animal was heading/facing in the preferred direction, expressed by the Gaussian peak of the directional tuning curve. The theta-rhythmic mode of spiking was closely related to the firing activity of local theta-bursting cells. We also found that 32% of anteroventral theta-bursting cells displayed a head-directional modulation of their spiking. This crossover between theta and head-directional signals indicates that anterior thalamus integrates information related to heading and movement, and may therefore actively modulate hippocampo-dencephalic information processing.

Oscillatory entrainment of thalamic neurons by theta rhythm in freely moving rats.

The anterior thalamic nuclei are assumed to support episodic memory with anterior thalamic dysfunction a core feature of diencephalic amnesia. To date, the electrophysiological characterization of this region in behaving rodents has been restricted to the anterodorsal nucleus. Here we compared single-unit spikes with population activity in the anteroventral nucleus (AV) of freely moving rats during foraging and during naturally occurring sleep. We identified AV units that synchronize their bursting activity in the 6-11 Hz range. We show for the first time in freely moving rats that a subgroup of AV neurons is strongly entrained by theta oscillations. This feature together with their firing properties and spike shape suggests they be classified as "theta" units. To prove the selectivity of AV theta cells for theta rhythm, we compared the relation of spiking rhythmicity to local field potentials during theta and non-theta periods. The most distinguishable non-theta oscillations in rodent anterior thalamus are sleep spindles. We therefore compared the firing properties of AV units during theta and spindle periods. We found that theta and spindle oscillations differ in their spatial distribution within AV, suggesting separate cellular sources for these oscillations. While theta-bursting neurons were related to the distribution of local field theta power, spindle amplitude was independent of the theta units' position. Slow- and fast-spiking bursting units that are selectively entrained to theta rhythm comprise 23.7% of AV neurons. Our results provide a framework for electrophysiological classification of AV neurons as part of theta limbic circuitry.

Differential regulation of synaptic plasticity of the hippocampal and the hypothalamic inputs to the anterior thalamus.

The hippocampus projects to the anterior thalamic nuclei both directly and indirectly via the mammillary bodies, but little is known about the electrophysiological properties of these convergent pathways. Here we demonstrate, for the first time, the presence of long-term plasticity in anterior thalamic nuclei synapses in response to high- and low-frequency stimulation (LFS) in urethane-anesthetized rats. We compared the synaptic changes evoked via the direct vs. the indirect hippocampal pathways to the anterior thalamus, and found that long-term potentiation (LTP) of the thalamic field response is induced predominantly through the direct hippocampal projections. Furthermore, we have estimated that that long-term depression (LTD) can be induced only after stimulation of the indirect connections carried by the mammillothalamic tract. Interestingly, basal synaptic transmission mediated by the mammillothalamic tract undergoes use-dependent, BDNF-mediated potentiation, revealing a distinct form of plasticity specific to the diencephalic region. Our data indicate that the thalamus does not passively relay incoming information, but rather acts as a synaptic network, where the ability to integrate hippocampal and mammillary body inputs is dynamically modified as a result of previous activity in the circuit. The complementary properties of these two parallel pathways upon anterior thalamic activity reveal that they do not have duplicate functions.

Hippocampal-anterior thalamic pathways for memory: uncovering a network of direct and indirect actions.

This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal-anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal-diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal-anterior thalamic systems for recollective rather than familiarity-based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimulation studies showing how the properties of the direct hippocampal-anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal-anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.