The posterior of the basolateral amygdala save fear extinction memories and feelings of reward

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When you expect a really bad experience to happen and then it doesn’t, it’s a distinctly positive feeling.

A new study of fear extinction training in mice may suggest why: The findings not only identify the exact population of brain cells that are key for learning not to feel afraid anymore, but also show these neurons are the same ones that help encode feelings of reward.

The study, published Jan. 14 in Neuron by scientists at MIT’s Picower Institute for Learning and Memory, specifically shows that fear extinction memories and feelings of reward alike are stored by neurons that express the gene Ppp1r1b in the posterior of the basolateral amygdala (pBLA), a region known to assign associations of aversive or rewarding feelings, or “valence,” with memories.

The study was conducted by Xiangyu Zhang, a graduate student, Joshua Kim, a former graduate student, and Susumu Tonegawa, Professor of Biology and Neuroscience at RIKEN-MIT Laboratory of Neural Circuit Genetics at the Picower Institute for Learning and Memory at MIT and Howard Hughes Medical Institute.

“We constantly live at the balance of positive and negative emotion,” Tonegawa said.

“We need to have very strong memories of dangerous circumstances in order to avoid similar circumstances to recur. But if we are constantly feeling threatened we can become depressed. You need a way to bring your emotional state back to something more positive.”

Overriding fear with reward

In a prior study, Kim showed that Ppp1r1b-expressing neurons encode rewarding valence and compete with distinct Rspo2-expressing neurons in the BLA that encode negative valence.

In the new study, Zhang, Kim and Tonegawa set out to determine whether this competitive balance also underlies fear and its extinction.

In fear extinction, an original fearful memory is thought to be essentially overwritten by a new memory that is not fearful. In the study, for instance, mice were exposed to little shocks in a chamber, making them freeze due to the formation of fearful memory.

But the next day, when the mice were returned to the same chamber for a longer period of time without any further little shocks, freezing gradually dissipated and hence this treatment is called fear extinction training.

The fundamental question then is whether the fearful memory is lost or just suppressed by the formation of a new memory during the fear extinction training.

While the mice underwent fear extinction training the scientists watched the activity of the different neural populations in the BLA. They saw that Ppp1r1b cells were more active and Rspo2 cells were less active in mice that experienced fear extinction.

They also saw that while Rspo2 cells were mostly activated by the shocks and were inhibited during fear extinction, Ppp1r1b cells were mostly active during extinction memory training and retrieval, but were inhibited during the shocks.

These and other experiments suggested to the authors that the hypothetical fear extinction memory may be formed in the Ppp1r1b neuronal population and the team went on to demonstrate this vigorously.

For this, they employed the technique previously pioneered in their lab for the identification and manipulation of the neuronal population that holds specific memory information, memory “engram” cells. Zhang labeled Ppp1r1b neurons that were activated during retrieval of fear extinction memory with the light-sensitive protein channelrhodopsin.

When these neurons were activated by blue laser light during a second round of fear extinction training it enhanced and accelerated the extinction. Moreover, when the engram cells were inhibited by another optogenetic technique, fear extinction was impaired because the Ppp1r1b engram neurons could no longer suppress the Rspo2 fear neurons. That allowed the fear memory to regain primacy.

These data met the fundamental criteria for the existence of engram cells for fear extinction memory within the pBLA Ppp1r1b cell population: activation and reactivation by recall and enduring and off-line maintenance of the acquired extinction memory.

These show basolateral amygdala neurons

Above: In the basolateral amygdala of a mouse, Ppp1r1b-expressing cells are stained green, while the cells in a fear extinction memory engram appear red. Image is credited to the researchers.

Because Kim had previously shown Ppp1r1b neurons are activated by rewards and drive appetitive behavior and memory, the team sequentially tracked Ppp1r1b cell activity in mice that eagerly received water reward followed by food reward followed by fear extinction training and fear extinction memory retrieval.

The overlap of Ppp1r1b neurons activated by fear extinction vs. water reward was as high as the overlap of neurons activated by water vs. food reward. And finally, artificial optogenetic activation of Ppp1r1b extinction memory engram cells was as effective as optogenetic activation of Ppp1r1b water reward-activated neurons in driving appetitive behaviors. Reciprocally, artificial optogenetic activation of water-responding Ppp1r1b neurons enhanced fear extinction training as efficiently as optogenetic activation of fear extinction memory engram cells. These results demonstrate that fear extinction is equivalent to bona fide rewards and therefore provide the neuroscientific basis for the widely held experience in daily life: omission of expected punishment is a reward.

What next?

By establishing this intimate connection between fear extinction and reward and by identifying a genetically defined neuronal population (Ppp1r1b) that plays a crucial role in fear extinction this study provides potential therapeutic targets for treating fear disorders like PTSD and anxiety, Zhang said.

From the basic scientific point of view, Tonegawa said, how fear extinction training specifically activates Ppp1r1b neurons would be an important question to address. More imaginatively, results showing how Ppp1r1b neurons override Rspo2 neurons in fear extinction raises an intriguing question about whether a reciprocal dynamic might also occur in the brain and behavior. Investigating “joy extinction” via these mechanisms might be an interesting research topic.

Funding: The research was supported by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute and the JPB Foundation funded the research.


The limbic system is vital for one’s normal functioning. This system acts as the center of emotions, behavior, and memory. It is also a contributor to the control of reactions to stress, attention and sexual instincts. It comprises a set of complex structures anatomically divided into the limbic cortex, cingulate gyrus, parahippocampal gyrus, hippocampal formation, dentate gyrus, hippocampus, subauricular complex, septal area, hypothalamus, and amygdala.[1]

The amygdala gets its name from its resemblance to almonds; it is an almond-shaped structure formed by many nuclei sorted into five major groups; basolateral nuclei, cortical-like nuclei, central nuclei, other amygdaloid nuclei, and extended Amygdala.[1]

The amygdala has been implicated in many diseases, such as depression,[2] sleep debt and anger,[3] as well as other neuropsychiatric diseases.

Structure and Function

The amygdala is an almond-shaped structure that lies in the temporal lobe, lying just beneath the uncus. The amygdala is diverse and complex in structure and comprises approximately 13 nuclei. T

hey further subdivide into extensive internuclear and intranuclear connections. These nuclei functionally sort into five major groups: basolateral nuclei, cortical-like nuclei, central nuclei, other amygdaloid nuclei, and extended amygdala.

Amygdala is one of the components of the limbic system, which is responsible for the control of emotions and behavior besides memory formation.

Anatomically, the amygdala lies at the anterior border of the hippocampal formation and the anterior aspect of lateral ventricle’s inferior horn where it merges with the peri-amygdaloid cortex, which forms part of the surface of the uncus.[1]

Amygdala manages the processing of information between prefrontal-temporal association cortices and the hypothalamus.

Amygdala has neural circuits to carry out its different functions with two major output pathways; Dorsal route via stria terminalis that projects to the septal area and hypothalamus, and the ventral route via the ventral amygdalofugal pathway which terminates in the septal area, hypothalamus, and the medial dorsal thalamic nucleus.[1] 

The amygdala also has connections with the basal ganglia circuit via its projections to the ventral pallidum and ventral striatum; these projections are relayed back to the cortex via the dorsomedial nucleus of the thalamus.[1] 

The basolateral circuit includes amygdala (especially the basolateral amygdala), the orbitofrontal and anterior temporal cortex, and in the thalamus, the magnocellular division of the dorsomedial nucleus (frontothalamic pathway), which serves as a relay back to the orbitofrontal cortex.[4] 

The circuit has been proposed as a substrate for the human ability to infer the intentions of others from their language, gaze, and gestures (Theory of mind and social cognition),[5] and helps with social interactions.

The amygdala also functions in regulating anxiety, aggression, fear conditioning, emotional memory, and social cognition.[1] Electrical stimulation of the amygdala evokes fear and anxiety responses in humans while lesions block certain types of unconditioned fear.

For example, rats with lesions in the amygdala show reduced freezing in response to cats, or cat hair, attenuated analgesia, heart rate responses to loud noise, and have reduced taste neophobia. However, amygdala lesions do not affect other measures of fear such as an open arm avoidance in an elevated plus maze in rats or analgesia to shock.

 The amygdala is also necessary for learning by fear, amygdala lesions disrupt the acquisition of both active avoidance (escape from fear), and passive avoidance of conditioned responses, but does not affect retention.

The amygdala processes not only emotions of fear and aversive stimuli, but it is also involved in conditioning using stimuli of appetite such as food, sex, and drugs. As for its role in memory, the activation of the amygdala has a modulatory effect on the acquisition and consolidation of memories that evoke an emotional response.[6]

Some parts of the amygdala have even more specific functions. The basolateral nucleus (BLA) is a cortical-like structure in the dorsal amygdala, and it regulates behavioral and physiological responses to stress.[7] 

The central amygdala (CeA) plays a crucial role in physiological responses to stressors, such as fearful stimuli, stressful stimuli, and some drug-related stimuli.[8] Meanwhile, the extended amygdala, named the bed nucleus of the stria terminalis (BNST), is involved in anxiety and stress.[9]

Embryology

At approximately the third week of gestation, the notochord induces neurulation, a process by which ectoderm above the notochord becomes the neural ectoderm which will later form the neural tube and crest. Noggin, chordin, BMP4, and FGF8 are some of the genes involved. The neural tube closes by week six. The rostral end will be the lamina terminalis. In addition to the spinal cord, the neural tube differentiates into three primary vesicles for the forebrain, midbrain, and hindbrain.

The forebrain further differentiates into the telencephalon and diencephalon; the midbrain continues to be the mesencephalon, and the hindbrain becomes the metencephalon and myelencephalon. These structures continue to differentiate into adult brain structures. The origin of the amygdaloid body or complex called the amygdala is traced to populations of diencephalic and telencephalic cells that form the floor of the lateral ventricle about three weeks after conception.[10] The telencephalon gives rise to the amygdala while neurons from the diencephalon migrate to further develop it.[11]

Blood Supply and Lymphatics

The anterior choroidal artery is the preterminal branch of the internal carotid and provides blood supply to the amygdala, and it is drained by the posterior choroidal vein which ends eventually to form the great cerebral vein that drains into the straight sinus.[12]

Astroglia podocytes form the blood-brain barrier by wrapping podocytes around capillaries. These cells protect the brain from toxins in the blood and facilitate nutrient transport to the neurons. Astroglia also forms a system of microscopic perivascular channels permeating the brain that transmit a cerebrospinal fluid (CSF)-like lymphatic vessels.

The system enables CSF to clear metabolic waste and distribute glucose, amino acids, lipids, and neurotransmitters. This system is most active during sleep, contributing to its restoration function. Arterial pulsation drives lymphatic flow, suggesting that exercise may also enhance it: aging, brain trauma, and ischemia decrease that CSF flow. Also, larger lymphatic vessels in the meninges help absorb interstitial fluid into the dural venous sinuses.[13][14]

Clinical Significance

The amygdala has been associated with many diseases, mainly neuropsychiatric. Many studies showed its effects on depression.[2][15] Others stressed the involvement of the amygdala in post-traumatic stress disorder as there is a bilateral reduction of the hippocampus and amygdala in PTSD.[16] Neural functioning among patients with PTSD is characterized by attenuated prefrontal inhibition on the limbic system, resulting in emotional dysregulation, and suggests that amygdala neurofeedback may not only be therapeutic for this patient group but may also be used as a future adjunctive treatment.[17] The amygdala and the limbic system might also be involved in chronic pain and has an association with the emotional effects of such pain.[18]


Source:
MIT

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