hippocampal neurons

Hippocampal neuron cultured for 3 weeks and stained for DNA in the nucleus (blue), the microtubule- associated protein MAP2 (green), and actin filaments (red). In mature neurons, MAP2 is present only in cell  bodies and dendrites and absent from axons. Actin filaments are present thoughout the neuron, including axons, but are especially enriched in dendritc spines, which appear as bright red dots along the dendrites.

Novel form of experience-dependent plasticity in the adult brain revealed

Research by a team of scientists from Cologne, Munich and Mainz has shown an unprecedented degree of connectivity reorganization in newly-generated hippocampal neurons in response to experience, suggesting their direct contribution to the processing of complex information in the adult brain.

The hippocampus is an anatomical area of the brain classically involved in memory formation and modulation of emotional behavior. It is also one of the very few regions in the adult brain where resident neural stem cells generate new neurons life-long, thus providing the hippocampal circuitry with an almost unique renewal mechanism important for information processing and mood regulation. In response to experience and voluntary exercise, the amount of new neurons that are incorporated into the hippocampus increases. Dr. Matteo Bergami from CECAD Cologne (Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases) has joined efforts with scientists from Ludwig Maximilians University Munich and the University Medical Center of Johannes Gutenberg University Mainz to investigate whether experience, rather than merely promoting neurogenesis, also modifies the connectivity of new neurons.

The scientists successfully showed that the pattern of connectivity of new neurons, namely the number and types of inputs received by each new neuron, is not prefigured in the adult brain but can be significantly altered in response to complex environmental conditions. In fact, following environmental enrichment (EE) the innervation by both local hippocampal interneurons and long distance projection cortical neurons was substantially increased. However, while the inhibitory inputs were largely transient, cortical innervation remained elevated even after ending the exposure to EE. These findings reveal that exposure to complex environmental stimuli as well as their deprivation regulates the way new neurons become incorporated into the preexisting circuitry and thus, their engagement into hippocampal-dependent tasks.

These findings significantly contribute to deepening our understanding of how the brain responds to experience and how external stimuli are translated into stable changes of neuronal connectivity. The results will not only help to decipher how complex learning processes modify the brain’s plasticity, but may also create an experimental basis for investigating the maladaptive changes in brain connectivity associated with neurological and neuropsychiatric disorders such as epilepsy, depression, anxiety, and posttraumatic stress.

The research group’s results represent a crucial step towards realizing the broader vision of CECAD at the University of Cologne, namely to understand the molecular and cellular basis of aging-associated diseases as a means to developing new effective therapeutic strategies.

Insulin-like Growth Factor Linked to Hippocampal Hyperactivity in Alzheimer's Disease

The mechanisms underlying the stability and plasticity of neural circuits in the hippocampus, the part of the brain responsible for spatial memory and the memory of everyday facts and events, has been a major focus of study in the field of neuroscience. Understanding precisely how a “healthy” brain stores and processes information is crucial to preventing and reversing the memory failures associated with Alzheimer’s disease (AD), the most common form of late-life dementia.

Hyperactivity of the hippocampus is known to be associated with conditions that confer risk for AD, including amnestic mild cognitive impairment. A new Tel Aviv University study finds that the insulin-like growth factor 1 receptor (IGF-1R), the “master” lifespan regulator, plays a vital role in directly regulating the transfer and processing of information in hippocampal neural circuits. The research reveals IGF-1R as a differential regulator of two different modes of transmission — spontaneous and evoked — in hippocampal circuits of the brain. The researchers hope their findings can be used to indicate a new direction for therapy used to treat patients in the early stages of Alzheimer’s disease.

The study was led by Dr. Inna Slutsky of TAU’s Sagol School of Neuroscience and Sackler School of Medicine and conducted by doctoral student Neta Gazit. It was recently published in the journal Neuron. “People who are at risk for AD show hyperactivity of the hippocampus, and our results suggest that IGF-1R activity may be an important contributor to this abnormality,” Dr. Slutsky concluded.

Resolving a controversy

“We know that IGF-1R signaling controls growth, development and lifespan, but its role in AD has remained controversial,” said Dr. Slutsky. “To resolve this controversy, we had to understand how IGF-1R functions physiologically in synaptic transfer and plasticity.”

Using brain cultures and slices, the researchers developed an integrated approach characterizing the brain system on different scales — from the level of protein interactions to the level of single synapses, neuronal connections and the entire hippocampal network. The team sought to address two important questions: whether IGF-1Rs are active in synapses and transduce signalling at rest, and how they affect synaptic function.

“We used fluorescence resonance energy transfer (FRET) to estimate the receptor activation at the single-synapse level,” said Dr. Slutsky. “We found IGF-1Rs to be fully activated under resting conditions, modulating release of neurotransmitters from synapses.”

While acute application of IGF-1 hormone was found to be ineffective, the introduction of various IGF-1R blockers produced robust dual effects — namely, the inhibition of a neurotransmitter release evoked by spikes, electrical pulses in the brain, while enhancement of spontaneous neurotransmitter release.

A test for Alzheimer’s?

“When we modified the level of IGF-1R expression, synaptic transmission and plasticity were altered at hippocampal synapses, and an increase in the IGF-1R expression caused an augmented release of glutamate, enhancing the activity of hippocampal neurons,” said Gazit.

“We suggest that IGF-1R small inhibitors, which are currently under development for cancer, be tested for reduction aberrant brain activity at early stages of Alzheimer’s disease,” said Dr. Slutsky.

The researchers are currently planning to study how IGF-1R signaling controls the stability of neural circuits over an extended timescale.

3D Compass in the Brain

Pilots are trained to guard against vertigo: a sudden loss of the sense of vertical direction that renders them unable to tell “up” from “down” and sometimes even leads to crashes. Coming up out of a subway station can produce similar confusion: For a few moments, you are unsure which way to go, until regaining your sense of direction. In both cases, the disorientation is thought to be caused by a temporary malfunction of a brain circuit that operates as a three-dimensional (3D) compass.

Weizmann Institute scientists have now for the first time demonstrated the existence of such a 3D compass in the mammalian brain. The study was performed by graduate student Arseny Finkelstein in the laboratory of Prof. Nachum Ulanovsky of the Neurobiology Department, together with Dr. Dori Derdikman, Dr. Alon Rubin, Jakob N. Foerster and Dr. Liora Las. As reported in Nature on December 3, the researchers have shown that the brains of bats contain neurons that sense which way the bat’s head is pointed and could therefore support the animal’s navigation in 3D space.

Navigation relies on spatial memory: past experience of different locations. This memory is formed primarily in a deep-seated brain structure called the hippocampal formation. In mammals, three types of brain cells, located in different areas of the hippocampal formation, form key components of the navigation system: “place” and “grid” cells, which work like a GPS, allowing animals to keep track of their position; and “head-direction” cells, which respond whenever the animal’s head points in a specific direction, acting like a compass. Much research has been conducted on place and grid cells, whose discoverers were awarded the 2014 Nobel Prize in Physiology or Medicine, but until recently, head-direction cells have been studied only in two-dimensional (2D) settings, in rats, and very little was known about the encoding of 3D head direction in the brain.

To study the functioning of head-direction cells in three dimensions, Weizmann Institute scientists developed a tracking apparatus that allowed them to video-monitor all the three angles of head rotation – in flight terminology, yaw, pitch and roll – and to observe the movements of freely-behaving Egyptian fruit bats. At the same time, the bats’ neuronal activity was monitored via implanted microelectrodes. Recordings made with the help of these microelectrodes revealed that in a specific sub-region of the hippocampal formation, neurons are tuned to a particular 3D angle of the head: Certain neurons became activated only when the animal’s head was pointed at that 3D angle.

The study also revealed for the first time how the brain computes a sense of the vertical direction, integrating it with the horizontal. It turns out that in the neural compass, these directions are computed separately, at different levels of complexity: The scientists found that head-direction cells in one region of the hippocampal formation became activated in response to the bat’s orientation relative to the horizontal surface, that is, facilitating the animal’s orientation in two dimensions, whereas cells responding to the vertical component of the bat’s movement – that is, a 3D orientation – were located in another region. The researchers believe that the 2D head-direction cells could serve for locomotion along surfaces, as happens in humans when driving a car, whereas the 3D cells could be important for complex maneuvers in space, such as climbing tree branches or, in the case of humans, moving through multi-story buildings or piloting an aircraft.

By further experimenting on inverted bats, those hanging head-down, the scientists were able to clarify how exactly the head-direction signals are computed in the bat brain. It turned out that these computations are performed in a way that can be described by an exceptionally efficient system of mathematical coordinates (the technical term is “toroidal”). Thanks to this computational approach used by their brain, the bats can efficiently orient themselves in space whether they are moving head up or down.

This research supports the idea that head-direction cells in the hippocampal formation serve as a 3D neural compass. Though the study was conducted in bats, the scientists believe their findings should also apply to non-flying mammals, including squirrels and monkeys that jump between tree branches, as well as humans. “Now this blueprint can be applied to other species that experience 3D in a more limited sense,” Prof. May-Britt Moser, one of the 2014 Nobel laureates, writes in the “News and Views” opinion piece that accompanies the Weizmann study in Nature.