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Neurogenesis in the Emotion-Processing Centre of the Brain

Credit: Photographee.eu

Credit: Photographee.eu

By Dhanisha Jhaveri

The generation of neurons during adulthood can affect our behaviour and alter our mood, so the discovery that this occurs in the amygdala could lead to new strategies for the treatment of anxiety-related disorders.

The discovery that some parts of the adult brain continue to generate new neurons has revolutionised our understanding of brain plasticity and opened up new remedial opportunities. However, whether this process occurs throughout the adult brain or is restricted to specific regions is still the subject of debate.

A new study has now added the amygdala, which controls fear and emotional memories, to the list of areas in which adult neurogenesis occurs. These findings not only advance our understanding of brain plasticity but may also lead to better treatments for anxiety-related disorders.

The Rise, Fall and Revival of Adult Neurogenesis

Adult neurogenesis has long been a highly debated topic in neuroscience, with the dogma “no new neurons in the adult brain” prevailing for the majority of last century. The strong belief among neuroscientists was that neuronal production in the brain stopped shortly after birth and that the neuronal circuitry in the adult brain was hard-wired and immutable.

This theory was challenged a little more than 50 years ago by Joseph Altman, who provided the first evidence that new neurons are indeed generated in the adult rodent brain. However, his discovery was largely discounted due to failed attempts by others in the field to replicate his findings.

Almost 30 years later pioneering studies led by Perry Bartlett and colleagues in Australia as well as Samuel Weiss’ group in Canada demonstrated that the adult mouse brain harboured neural stem or precursor cells with the capacity to generate neuronal progeny. These discoveries paved the way for a large number of studies which showed that these endogenous pools of stem cells proliferate and subsequently differentiate to generate new neurons that become functionally active and integrate into the existing brain circuitry. During this time, immense work has been done to determine the roles that these newborn neurons play, as well as the mechanisms that regulate neurogenesis.

The hippocampus is a key area of the brain where the occurrence of adult neurogenesis has been firmly established. It has also remained in the research spotlight since the hippocampus has been implicated as a critical regulator of the neural circuitry underlying both cognition and mood. Various studies have shown that neurons in the newborn hippocampus have special properties: they are easily excitable and therefore more active than their already mature counterparts, which in turn can profoundly influence the circuitry and functions of this brain region.

Research efforts aimed at understanding the regulation and function of hippocampal neurogenesis have also been fuelled by a 2013 study which proposed that approximately 700 new neurons are added to the human hippocampus every day, and that there is a large turnover of hippocampal neurons during adult life. Accumulating evidence in animal models has shown that inhibition or depletion of newborn neurons results in deficits in spatial navigation, learning and memory. In addition, there is growing evidence that hippocampal neurogenesis is compromised in pre-clinical models of anxiety and depression, and that it serves as a primary target for the actions of antidepressants. Thus the plasticity offered by adult neurogenesis has become central to our understanding of many brain functions.

Driving the production of new neurons in the hippocampus are pools of quiescent or latent neural stem cells. Our studies have uncovered that these large populations of quiescent stem cells can be activated by a number of neurochemical and environmental signals. However, whether such latent stem cell populations are also present in other brain regions, and whether they generate functional new neurons, has only recently been investigated.

A New Neurogenic Niche in the Adult Brain

Although adult neurogenesis has been proposed for other regions of the adult brain, researchers still know very little about the characteristics of any resident stem or precursor cells, their potential to differentiate, mature and integrate into the local circuitry, and their functional contribution. Given the pivotal role of the amygdala in the acquisition, consolidation and expression of emotional memories, there has been considerable interest in confirming the existence and possible functional role of neurogenesis in this region.

The amygdala is a crucial player in a host of anxiety-related disorders, including generalised anxiety, post-traumatic stress and phobias. Moreover, antidepressants that are widely used for the treatment of many of these disorders also enhance neurogenesis in the adult hippocampus.

These findings prompted us to investigate whether the adult amygdala, like the hippocampus, also harbours a resident pool of neural stem cells and whether these cells proliferate and generate functional new neurons. In a collaborative effort involving the research groups of Perry Bartlett and Pankaj Sah at the Queensland Brain Institute, we set out to determine whether the amygdala is truly a neurogenic region in the adult brain.

Direct evidence of neurogenesis required us to employ traditional anatomical, cell culture and physiological techniques along with modern genetic tools to map the fate of the neuronal progeny of resident stem cells. Excitingly, we found proliferating stem cells in the adult mouse amygdala, albeit in far fewer number than in the hippocampus. We not only observed the presence of new cells, but also their conversion to neurons.

To confirm that the new neurons were being generated from the resident pool of stem cells, we injected mice with a retrovirus that only infects cells that are undergoing division to form new cells, and observed the expression of a green fluorescently tagged reporter gene in neurons 6–8 weeks later. This, together with the use of a genetically modified mouse in which stem cells and their progeny were selectively tagged, provided convincing evidence for the generation of new neurons in the adult amygdala.

However, it has often been said that the standard of proof is proportional to the importance and novelty of a claim – in other words, an extraordinary claim requires extraordinary evidence. By definition, a cell is not a bona fide neuron unless it “behaves” like a neuron and produces and propagates the electrical action potentials via which cells in the nervous system relay information. Hence, we also measured the electro­physiological properties and found, to our surprise, that the newborn neurons in the amygdala inhibited other neurons in the circuitry. This is in contrast to the excitatory nature of newborn neurons generated in the hippocampus, thereby indicating that electrical properties of adult-born neurons are distinct and region-specific.

Understanding the Role and Function of Newborn Neurons in the Amygdala

Having established the amygdala as a bona fide neurogenic region in the adult mouse brain, the next important challenges are to determine the functional connections made by these newborn neuronsand their role in regulating the amygdala’s circuitry and function.

Answers to these questions have enormous implications for understanding the regulation of fear and fearful memories. The amygdala plays a key role in the process by which we learn to fear by associating a stimulus with a frightening event. For example, a person who is bitten by a neighbour’s dog will experience the classic flight-or-fight response – increased heart rate, dry mouth and sweaty palms – every time he or she walks past that property. This is fear conditioning, whereby an otherwise neutral stimulus (the neighbour’s yard) elicits a heightened response based on past experience. Understanding how newborn neurons contribute to this process is the first step in the design of better strategies to treat disorders of fear processing.

Using the research toolbox that we have already developed together with emergent new strategies to selectively and precisely control the activity of newborn neurons, we are now positioned to unravel the connections made by these new neurons, their contribution to anxiety and stress-related behaviours, and their role in mediating the anxiolytic effects of antidepressants.

Together, these experiments will provide the first understanding of the functional role of newborn neurons in the amygdala. In particular, they will show if stress, and pharmacological agents used for the treatment of anxiety-related disorders, act by modulating neurogenesis in the amygdala, thereby providing a better understanding of the pathogenesis of these disorders.

Thus, from being a contentious topic around 50 years ago, neuroscientists today agree that adult neurogenesis confers a unique mode of plasticity in the adult mammalian brain. However, the latest findings have led us to further uncharted territory in the landscape of adult neurogenesis. With growing understanding of neural stem cell biology and the functional roles of new neurons, the field is looking forward to tapping this plasticity in order to develop novel approaches to ameliorate neuropsychiatric disorders.


Dr Dhanisha Jhaveri is a Mater Research Foundation Senior Research Fellow at the Mater Research Institute and a Group Leader at the Queensland Brain Institute, The University of Queensland, and co-author of the research published in Molecular Psychiatry (https://tinyurl.com/yd46tldh).