Tamas Freund

Institute of Experimental Medicine, Budapest, Hungary

GABAergic inhibitory neurons fundamentally shape the activity and plasticity of cortical circuits. A major subset of these neurons contains somatostatin (SOM); these cells play crucial roles in neuroplasticity, learning, and memory in many brain areas including the hippocampus, and are implicated in several neuropsychiatric diseases and neurodegene...

Hippocampal theta oscillations orchestrate faster beta-to-gamma oscillations facilitating the segmentation of neural representations during navigation and episodic memory. Supra-theta rhythms of hippocampal CA1 are coordinated by local interactions as well as inputs from the entorhinal cortex (EC) and CA3 inputs. However, theta-nested gamma-band ac...

The human hippocampus plays a central role in learning and memory functions, and is implicated in several neurological and psychiatric disorders linked to different subpopulations of its neurons. However, understanding the complex workings of the human hippocampus requires computational models with accurate neural data. Although the total number of...

The hippocampal formation of the mammalian brain is essential in learning and memory processes. Its pyramidal cells are precisely regulated by different types of GABAergic interneurons. Somatostatin (SOM)-containing inhibitory interneurons play crucial roles in neuroplasticity, learning and memory in many brain areas including the hippocampus, and...

Episodic learning and memory retrieval are dependent on hippocampal theta oscillation, thought to rely on the GABAergic network of the medial septum (MS). To test how this network achieves theta synchrony, we recorded MS neurons and hippocampal local field potential simultaneously in anesthetized and awake mice and rats. We show that MS pacemakers...

Hippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated ('replayed'), either in the same or reversed order, during bursts of activity (sharp wave-ripples; SWRs) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and...

Ascending serotonergic/glutamatergic projection from the median raphe region (MRR) to the hippocampal formation regulates both encoding and consolidation of memory and the oscillations associated with them. The firing of various types of MRR neurons exhibits rhythmic modulation coupled to hippocampal oscillatory activity. A possible intermediary be...

Hippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated (``replayed'), either in the same or reversed order, during bursts of activity (sharp wave-ripples; SWRs) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and...

Hippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated ("replayed"), either in the same or reversed order, during bursts of activity (sharp wave-ripples; SWRs) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and...

Anatomically and biophysically detailed data-driven neuronal models have become widely used tools for understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that...

Episodic learning and memory retrieval are critically dependent on a hippocampal 4-12 Hz oscillatory 'clock' signal, the theta oscillation. This clock is largely externally paced, by a network of GABAergic neurons in the medial septum (MS). Theoretical studies suggested a range of hypotheses how this network may achieve theta synchrony; however, ex...

Most biological brains, as well as artificial neural networks, are capable of performing multiple tasks [1]. The mechanisms through which simultaneous tasks are performed by the same set of units are not yet entirely clear. Such systems can be modular or mixed selective through some variables such as sensory stimulus [2,3]. Based on simple tasks st...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Basal forebrain cholinergic neurons (BFCNs) modulate synaptic plasticity, cortical processing, brain states and oscillations. However, whether distinct types of BFCNs support different functions remains unclear. Therefore, we recorded BFCNs in vivo, to examine their behavioral functions, and in vitro, to study their intrinsic properties. We identif...

Anatomically and biophysically detailed data-driven neuronal models have become widely used tools for understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that...

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aβ) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APPNL-F mice, APP gene was humanized and contains two familial AD mutations, and APP–unlike other mouse models of AD–is driven by the endogenou...

Significance This work provides evidence that soluble and oligomeric amyloid protein stokes neuronal inflammation during the earliest stages of Alzheimer’s disease. Identifying neuron-derived factors that engage the brain’s immune system will provide insight into how vulnerable neurons might interact with other immune cells to propagate cytotoxic s...

Keeping tabs on bad experiences Identifying the neural basis underlying how we acquire, process, and store negative experiences could help the search for effective treatments for mood disorders. Szőnyi et al. used a range of neuroscientific tools to elucidate the role of a specific neural circuit that originates in the median raphe region of the mu...

The neural circuit linking the basal ganglia, the cerebellum and the cortex through the thalamus plays an essential role in motor and cognitive functions. However, how such functions are realized by multiple loop circuits with neurons of multiple types is still unknown. In order to investigate the dynamic nature of the whole-brain network, we built...

Basal forebrain cholinergic neurons (BFCN) densely innervate the forebrain and modulate synaptic plasticity, cortical processing, brain states and oscillations. However, little is known about the functional diversity of cholinergic neurons and whether distinct types support different functions. To examine this question we recorded BFCN in vivo, to...

What inhibits the inhibitors? In the hippocampus, each memory trace is encoded by a specific subset of pyramidal cells. The other pyramidal cells must be actively excluded from the memory encoding process by inhibition, which is done by selective dendrite-targeting interneurons. Szőnyi et al. found that γ-aminobutyric acid–releasing (GABAergic) cel...

Growing evidence gathered from transgenic animal models of Alzheimer’s disease (AD) indicates that the intraneuronal accumulation of amyloid-β (Aβ) peptides is an early event in the AD pathogenesis, producing cognitive deficits before the deposition of insoluble plaques. Levels of soluble Aβ are also a strong indicator of synaptic deficits and conc...

Every neuron is part of a network, exerting its function by transforming multiple spatiotemporal synaptic input patterns into a single spiking output. This function is specified by the particular shape and passive electrical properties of the neuronal membrane, and the composition and spatial distribution of ion channels across its processes. For a...

Electrophysiological features used for optimization of pyramidal neurons. (DOCX)

CA1 pyramidal neuron and interneuron active properties. Morphologies of a pyramidal neuron (left) and an interneuron (right), with a schematic indication of channels’ distribution on the soma, axon, and dendrites. (DOCX)

Electrophysiological features used for optimization of int cAC cells. (DOCX)

Electrophysiological features used for optimization of int cNAC cells. (DOCX)

Morphological classes and e-types of the optimized pyramidal cells (left) and interneurons (right). (DOCX)

Spearman correlation coefficient between peak conductance values from cNAC interneuron models. Only conductances with at least one significant correlation coefficient >|0.25| (gray cells) are shown. The p value corresponding to each coefficient is indicated in italics. (DOCX)

Electrophysiological features used for optimization of int bAC cells. (DOCX)

Spearman correlation coefficient between peak conductance values from pyramidal cell models. Only conductances with at least one significant correlation coefficient >|0.25| (gray cells) are shown. The p value corresponding to each coefficient is indicated in italics. (DOCX)

Spearman correlation coefficient between peak conductance values from cAC interneuron models. Only conductances with at least one significant correlation coefficient >|0.25| (gray cells) are shown. The p value corresponding to each coefficient is indicated in italics. (DOCX)

Spearman correlation coefficient between peak conductance values from bAC interneuron models. Only conductances with at least one significant correlation coefficient >|0.25| (gray cells) are shown. The p value corresponding to each coefficient is indicated in italics. (DOCX)

The basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter. Yet, we find that mouse hippocampal cholinergic terminals invariably establish GABAergic synapses, and their cholinergic vesicles dock at those synapses only. We demonstrate that these synapses do not co...

Animals build a model of their surroundings on the basis of information gathered during exploration. Rearing on the hindlimbs changes the vantage point of the animal, increasing the sampled area of the environment. This environmental knowledge is suggested to be integrated into a cognitive map stored by the hippocampus. Previous studies have found...

Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7) are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the reg...

The basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter, acetylcholine. Yet, using immune-electron tomographic, molecular anatomical, optogenetic and physiological techniques, we find that mouse hippocampal cholinergic terminals invariably establish synapses a...

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted e...

Representative video of the locomotion on day 1. Video shows one representative example from the stimulation control (see methods; this is a case of no stimulation) and another from the central stimulation group (see methods; intermittent stimulation at 50Hz theta burst frequency). (AVI)

Behavioral effects of intermittent 50Hz theta bursts and continuous 20Hz stimulation. (a) Time course of exploration and ambulation shown in time-bins representing the stimulation and non-stimulation periods of intermittent stimulation at 50Hz theta burst frequency. (b) Exploration and ambulation in mice submitted to continuous 20Hz stimulation in...

Representative pictures of the periaqueductal gray after c-Fos immunohistochemistry. Pictures were taken around -4.36 mm from the Bregma. Scalebar is 100μm. Group1: home cage controls; Group2: no ChR2 controls (transferred for 5 min to the conditioning cage, no ChR2 expression); Group3: no light controls (cage transfer, robust ChR2 expression, not...

Behavior in control groups was not different from that seen in intact mice. The scale of Y-axes is similar to those used for experimental groups (see Figs 1 and 3). (a) No rhythmic changes in exploration or ambulation were observed. Note that the scoring of behavior was time-structured in all groups as for effective intermittent stimulations (as in...

Representative pictures of the locomotion on day 1. Track visualization of the distance travelled during the fear conditioning. Higher velocity is indicated by bright color (yellow), slower movements or rest is signed by dark red (a,b). Heat maps represent the average time spent (s) at each location (c,d), blue meaning less time and red marking the...

Raw data of the experiment. File contains all data underlying the findings described in the manuscript and grouped by the number of the figures. (XLS)

The median raphe region (MRR, which consist of MR and paramedian raphe regions) plays a crucial role in regulating cortical as well as subcortical network activity and behavior, while its malfunctioning may lead to disorders, such as schizophrenia, major depression, or anxiety. Mouse MRR neurons are classically identified on the basis of their sero...

In vivo and in vitro multichannel field and somatic intracellular recordings are frequently used to study mechanisms of network pattern generation. When interpreting these data, neurons are often implicitly considered as electrotonically compact cylinders with a homogeneous distribution of excitatory and inhibitory inputs. However, the actual distr...

Jiang et al. (Research Article, 27 November 2015, aac9462) describe detailed experiments that substantially add to the knowledge of cortical microcircuitry and are unique in the number of connections reported and the quality of interneuron reconstruction. The work appeals to experts and laypersons because of the notion that it unveils new principle...

Synaptic reorganization in the epileptic hippocampus involves altered excitatory and inhibitory transmission besides the rearrangement of dendritic spines, resulting in altered excitability, ion homeostasis, and cell swelling. The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role...

Key points: To understand how a network operates, its elements must be identified and characterized, and the interactions of the elements need to be studied in detail. In the present study, we describe quantitatively the connectivity of two classes of inhibitory neurons in the hippocampal CA3 area (parvalbumin-positive and cholecystokinin-positive...

Key points: •Median raphe is a key subcortical modulatory centre involved in several brain functions e.g. regulation of sleep-wake cycle, emotions and memory storage. •A large proportion of median raphe neurones are glutamatergic and implement a radically different mode of communication than serotonergic cells, but their in vivo activity is unknow...

Sharp-wave-ripple complexes (SWRs) and interictal-spikes are physiological and pathological forms of irregularly occurring transient high activity events in the hippocampal EEG. They share similar features and carry high-frequency oscillations with different spectral features. Recent results reveal similarities and differences in the generation of...

The median raphe region (MRR) is thought to be serotonergic and plays an important role in the regulation of many cognitive functions. In the hippocampus (HIPP), the MRR exerts a fast excitatory control, partially through glutamatergic transmission, on a subpopulation of GABAergic interneurons that are key regulators of local network activity. Howe...

Significance Theta oscillations are a prominent rhythm of the brain occurring during active behavior and rapid eye movement sleep and thought to provide the temporal frame for the encoding of information. Acetylcholine modulation is a major player in hippocampal theta rhythm, as demonstrated by lesion and pharmacological manipulations of cholinergi...

Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential in memory formation. To understand the mechanisms underlying the initiation of irregularly occurring SWRs and the generation of periodic ripples, we selectively manipulated different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs and...

The construction of biologically relevant neuronal models as well as model-based analysis of experimental data often requires the simultaneous fitting of multiple model parameters, so that the behavior of the model in a certain paradigm matches (as closely as possible) the corresponding output of a real neuron according to some predefined criterion...

Alkamides are one of the most important constituents of lipophilic extracts of Echinacea angustifolia roots. These compounds play an important role in the versatile pharmacological actions of this plant. The present study aimed to compare the concentrations of isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (DTAI) in brain and periepi...

Three functionally different populations of perisomatic interneurons establish GABAergic synapses on hippocampal pyramidal cells: parvalbumin (PV)-containing basket cells, type 1 cannabinoid receptor (CB1)-positive basket cells both of which target somata, and PV-positive axo-axonic cells that innervate axon initial segments. Using electron microsc...

Sharp wave-ripples and interictal events are physiological and pathological forms of transient high activity in the hippocampus with similar features. Sharp wave-ripples have been shown to be essential in memory consolidation, whereas epileptiform (interictal) events are thought to be damaging. It is essential to grasp the difference between physio...

The construction of biologically relevant neuronal models as well as model-based analysis of experimental data often requires the simultaneous fitting of multiple model parameters, so that the behavior of the model in a certain paradigm matches (as closely as possible) the corresponding output of a real neuron according to some predefined criterion...

In the hippocampus, parvalbumin-expressing basket (BC) and axo-axonic cells (AAC) show different discharge patterns during distinct network states, but the cellular mechanisms underlying these differences are not well understood. Using whole-cell patch-clamp techniques, we investigated the single-cell properties and excitatory synaptic features of...

Neuroligin 2 is a postsynaptic protein that plays a critical role in the maturation and proper function of GABAergic synapses. Previous studies demonstrated that deletion of neuroligin 2 impaired GABAergic synaptic transmission, whereas its overexpression caused increased inhibition, which suggest that its presence strongly influences synaptic func...

Hippocampal sharp waves and the associated ripple oscillations (SWRs) are implicated in memory processes. These network events emerge intrinsically in the CA3 network. To understand cellular interactions that generate SWRs, we detected first spiking activity followed by recording of synaptic currents in distinct types of anatomically identified CA3...

Several distinct patterns of population activity can be recorded in the hippocampus in vivo. These neural activity patterns depend on the behavioral state of the animal, and include theta-modulated gamma oscillations as well as low-level irregular activity with periodically occurring large-amplitude sharp wave-ripple (SWR) events. During SWRs, neur...

Members of the transient receptor potential (TRP) cation channel family play important roles in several neuronal functions. To understand the precise role of these channels in information processing, their presence on neuronal elements must be revealed. In this study, we investigated the localization of TRPC6 channels in the adult hippocampal forma...

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using...

We investigated the toxicity, psychotropic side effects and anxiolytic potential of an Echinacea angustifolia extract that produced promising effects in laboratory tests performed earlier. Rats were studied in the elevated plus-maze, conditioned fear, open-field, object recognition and conditioned place preference tests. Toxicity was studied in rat...

We investigated the toxicity, psychotropic side effects and anxiolytic potential of an Echinacea angustifolia extract that produced promising effects in laboratory tests performed earlier. Rats were studied in the elevated plus‐maze, conditioned fear, open‐field, object recognition and conditioned place preference tests. Toxicity was studied in rat...

Although endocannabinoids have emerged as essential retrograde messengers in several forms of synaptic plasticity, it remains controversial whether they mediate long-term depression (LTD) of glutamatergic synapses onto excitatory and inhibitory neurons in the hippocampus. Here, we show that parvalbumin- and somatostatin/metabotropic glutamate recep...

The two main glutamatergic pathways to the CA1 area, the Schaffer collateral/commissural input and the entorhinal fibers, as well as the local axons of CA1 pyramidal cells innervate both pyramidal cells and interneurons. To determine whether these inputs differ in their weights of activating GABAergic circuits, we have studied the relative proporti...

GABA (gamma-aminobutyric-acid), the main inhibitory neurotransmitter in the adult brain, exerts depolarizing (excitatory) actions during development and this GABAergic depolarization cooperates with NMDARs (N-methyl-D-aspartate receptors) to drive spontaneous synchronous activity (SSA) that is fundamentally important for developing neuronal network...

Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters such as glutamate or GABA, yet they act in profoundly u...

The endocannabinoid system plays a central role in retrograde synaptic communication and may control the spread of activity in an epileptic network. Using the pilocarpine model of temporal lobe epilepsy we examined the expression pattern of the Type 1 cannabinoid receptor (CB1-R) in the hippocampi of CD1 mice at survival times of 2 hours, 1 day, 3...

Early γ-aminobutyric acid mediated (GABAergic) synaptic transmission and correlated neuronal activity are fundamental to network formation; however, their regulation during early postnatal development is poorly understood. Nitric oxide (NO) is an important retrograde messenger at glutamatergic synapses, and it was recently shown to play an importan...