Limbic System

• Limbic Lobe: Functional and anatomical unit that encircles the brainstem and corpus callosum like a border (“limbus” → border). Part of the limbic system and includes cortical areas that encircle the corpus callosum and extend into the medial temporal lobe, integrating sensory, emotional, and memory-related processes. (Functions of the hippocampus “HOME”)

  • Homeostasis: Regulates autonomic and neuroendocrine control. (Hypothalamus)

  • Olfaction: Processes smells linked to memories and emotions. (Olfactory Cortex)

  • Memory: Key role in forming, consolidating, and retrieving memories. (Hippocampal Formation)

  • Emotions and Drives: Mediates emotional responses and motivation. (Amygdala)

Hippocampus

Location and Anatomy

• Medial Temporal Lobe: The hippocampus lies within the medial temporal lobe, beneath the temporal horn of the lateral ventricle. It is closely associated with other limbic structures, including the amygdala, fornix and entorhinal cortex.

  • Anterior: The amygdala is connected to the head of the hippocampus trough a thin tract.

  • Posterior: Merges into the fornix, a major output pathway.

• Orientation and Folding: The hippocampus begins near the amygdala in the anterior medial temporal lobe and extends posteriorly, folding into itself. It forms a C-shaped curve when viewed in a sagittal or coronal plane.

• Cortical Origin: The hippocampus is part of the archicortex, an evolutionarily older form of cortex compared to the six-layered neocortex. The archicortex of the hippocampus typically has three layers:

  • Molecular Layer: Receives inputs.

  • Pyramidal Layer: Contains principal excitatory neurons.

  • Polymorphic Layer: Sends outputs.

• Dentate Gyrus: Part of the hippocampus that serves as a input gateway, forming the first stage of the hippocampal memory circuit. It receives and processes information from the entorhinal cortex and transmits it further to the CA3 region of the hippocampus. Its primary function is pattern separation, which allows the brain to distinguish between similar but distinct events or experiences by creating unique memory representations. This ability is critical for maintaining accurate and organised memory storage.

  • Pattern Separation: The dentate gyrus ensures that overlapping or similar inputs (e.g., two visits to the same room with slight differences) are stored as separate, distinct memories. This prevents confusion between similar experiences and enables precise recall of specific events.

  • Neurogenesis: The dentate gyrus is one of the few regions in the adult brain capable of neurogenesis (generation of new neurons). These new neurons contribute to the brain's plasticity, enhancing its ability to adapt, learn, and form new memories.

• Cornu Ammonis (CA): The pyramidal cell layers of the hippocampus that can be divided into four subfields each with distinct cellular compositions and functions. Together, these regions are responsible for processing and transmitting information within the hippocampus to enable memory encoding, storage and retrieval.

  • CA1: Acts as the primary output region of the hippocampus by integrating processed information from CA3 and relaying it to the subiculum and entorhinal cortex. Also crucial for consolidating memories.

  • CA2: Plays a specialised role in encoding social memory and processing contextual information.

  • CA3: Contains recurrent connections that facilitate associative learning and memory storage, performing pattern completion, thus enabeling individuals to retrieve entire memories from partial or incomplete cues.

• Subiculum: Part of the hippocampus that serves as a gateway for hippocampul output, sending processed information to the entorhinal cortex, fornix, hypothalamus, thalamus, and prefrontal cortex, among other areas. It serves as the final processing stage for information traveling through the hippocampus before it reaches higher brain centers for further integration and long-term storage.

Connections of the Hippocampus

Input Connections

• Entorhinal Cortex: Region of the medial temporal lobe that serves as a critical hub for information exchange between the neocortex and the hippocampus. It acts as the primary gateway for sensory, spatial, and contextual information entering and leaving the hippocampus, enabling memory formation, consolidation, and retrieval.

Output Connections

• Fornix: A C-shaped white matter tract in the brain that serves as a major output pathway of the hippocampus, connecting it to various subcortical structures. It acts as a communication highway, carrying signals from the hippocampus to regions such as the mammillary bodies and anterior thalamus, enabling memory processing and consolidation of these brain regions.

  • Mammillary Bodies: Rounded structures at the base of the brain within the posterior hypothalamus that serve as a relay station in the memory circuit, connecting the hippocampus to the anterior thalamus. They play a vital role in memory consolidation and recall, particularly for episodic memory.

  • Anterior Thalamic Nuclei: group of thalamic nuclei located in the anterior part of the thalamus. They are key components of the Papez Circuit, relaying processed memory information from the mammillary bodies to the cingulate cortex, where cognitive and emotional aspects of memory are integrated. The anterior thalamus supports the encoding, consolidation, and retrieval of memories, especially episodic memory.

Memory Circuits

Within the Hippocampus

Entorhinal Cortex → Dentate Gyrus (Pattern Separation) → CA3 (Pattern Completion) → CA1 (Memory Integration) → Subiculum or Entorhinal Cortex

• Trisynaptic Pathway: Internal circuitry of the hippocampus that is responsible for processing and relaying information to encode episodic memories and integrate sensory and spatial information. This pathway transforms raw sensory and contextual input into processed memory traces that can be stored and retrieved later.

  • Entorhinal Cortex: Main input and output hub of the hippocampus. It receives multimodal sensory information from cortical regions (e.g., auditory, visual, and somatosensory cortices) and integrates spatial and contextual information. Projects directly to the dentate gyrus and CA3 region.

  • Dentate Gyrus: Receives input and relay signals to the next stage - CA3.

  • CA3: From the dentate gyrus, processed input reaches CA3, which plays a key role in pattern completion, reconstructing full memories from partial cues. This region is also features recurrent excitatory connections, enabling associative learning and the formation of richly interconnected memory traces.

  • CA1: Integrates and refines processed signals from CA3 with additional input from the entorhinal cortex and sends output to the subiculum and entorhinal cortex, linking hippocampal processing back to the broader brain.

  • Subiculum: The subiculum receives processed information from CA1 and acts as the primary output structure of the hippocampus. It transmits hippocampal output to multiple brain regions, including:

    • Entorhinal Cortex: To complete the hippocampal loop.

    • Fornix: For relaying signals to the mammillary bodies, hypothalamus, and anterior thalamus.

    • Prefrontal Cortex: For higher-order cognitive functions.

  • Entorhinal Cortex: Information processed by the subiculum is returned to the entorhinal cortex, completing the hippocampal loop. The entorhinal cortex sends this output back to the neocortex for long-term memory storage.

Outside the Hippocampus

Hippocampus → Fornix → Mammillary Bodies → Anterior Thalamus → Cingulate Gyrus → Entorhinal Cortex → Back to Hippocampus.

• Papez Circuit: Circuit of brain regions within the limbic system that is essential for memory formation, memory consolidation, and the integration of emotions with memory. It links the hippocampus, mammillary bodies, anterior thalamus, cingulate gyrus, and entorhinal cortex, forming a loop that processes sensory, spatial, and emotional information. By connecting these regions, this circuit enables the transformation of short-term memories into long-term memories and the association of emotional significance with experiences.

  • Hippocampus: Starting point of the circuit where encoding of sensory, spatial and contextual information into a cohesive memory representation takes place.

  • Fornix: Acts as a communication highway between the hippocampus and the mammillary bodies.

  • Mammillary Bodies: Relay station for hippocampal signals that integrates and processes memory-related information.

  • Anterior Thalamus: Relays processed information from the mammillary bodies to the cingulate cortex and plays a role in spatial and episodic memory by linking sensory and emotional data.

  • Cingulate Gyrus: Integrates memory with emotions, attention, and higher cognitive processes and facilitates conscious recall of events and experiences.

  • Entorhinal Cortex: Acts as a hub for sensory information entering and leaving the hippocampus and relays signals back to the hippocampus to complete the circuit.

Lesions of the Hippocampus

Declarative Memory

• Declarative Memory: Memories that can be consciously recalled and expressed verbally, including episodic and semantic memory.

  • Episodic Memory: Memory of specific events, including their spatial, temporal and contextual details.

    • Dependence on Hippocampus: The hippocampus is essential for encoding, consolidating, and retrieving episodic memories.

    • Effects of Hippocampal Lesions: Lesions result in severe deficits:

      • Anterograde Amnesia: Inability to form new episodic memories after the lesion.

      • Retrograde Amnesia (Partial): Loss of recent episodic memories formed just before the lesion, as these memories may not yet be consolidated into the neocortex. Older episodic memories (already consolidated) often remain intact, as they are stored in distributed cortical areas.

  • Semantic Memory: Memory for general knowledge, facts, and concepts.

    • Dependence on Hippocampus: Semantic memory formation initially requires the hippocampus, as new knowledge relies on episodic-like encoding. However, over time, as semantic memories are consolidated, they become largely independent of the hippocampus, relying on the lateral temporal cortex and other neocortical areas.

    • Effects of Hippocampal Lesions: Established semantic memories are typically preserved, as they are stored outside the hippocampus. However, lesions impair the acquisition of new semantic knowledge because new learning depends on hippocampal processing.

Non-Declarative Memory

• Non-Declarative Memory: Unconscious, implicit memory processes that do not require conscious recall. It includes procedural memory, habits, priming, and classical conditioning.

• Dependence on Hippocampus: Non-declarative memory is not reliant on the hippocampus. Instead, it depends on other brain structures:

  • Basal Ganglia: Supports procedural memory and habit formation.

  • Cerebellum: Involved in motor learning and coordination.

  • Amygdala: Critical for emotional conditioning and implicit emotional memories.

• Effects of Hippocampal Lesions: Non-declarative memory remains intact. Patients like H.M. can learn new motor skills (e.g., mirror-drawing) without conscious recollection of the learning process.

Case Study - H.M.

• Patient H.M. (Henry Molaison) underwent bilateral removal of the hippocampus to treat epilepsy. His case provided key insights into the distinction between declarative and non-declarative memory:

  • Episodic Memory: H.M. could not form new episodic memories (e.g., he forgot meeting new people moments after an interaction). He also lost episodic memories formed shortly before the surgery.

  • Semantic Memory: Retained general knowledge acquired before the surgery (e.g., he knew the meaning of words and general facts). Struggled to learn new semantic information, such as the names of new objects or concepts.

  • Non-Declarative Memory: H.M. could learn new motor skills, such as completing the mirror-drawing task. He showed improvement with practice but had no conscious recollection of ever performing the task.

Amygdala

Location and Anatomy

• Location: The amygdala is located at the most medial tip of the medial temporal lobe, deep within the brain beneath the cortical surface. It is situated just in front of the hippocampus, with which it has strong functional and anatomical connections. The uncus, a protrusion on the medial temporal lobe, serves as a surface landmark to locate the amygdala underneath.

• The amygdala is not a single structure but rather a collection of nuclei, each with distinct functions and connections and is broadly divided into two main complexes:

  • Basal Complex: responsible for processing sensory inputs, associating them with emotions (e.g., fear or reward), and determining appropriate responses. Sends processed information to the central complex, hippocampus, and prefrontal cortex for further integration. (Determines emotional relevance)

  • Central Complex: generates behavioral and physiological responses to emotional stimuli, such as the fight-or-flight response, and regulates autonomic functions, including heart rate, respiration, and hormonal release via connections to the hypothalamus. (Translates emotional relevance into physiological or behavioural response)

  Together, these systems ensure that emotional stimuli are rapidly assessed and translated into appropriate actions.

Inputs to the Amygdala

Sensory Inputs

• Olfactory Bulb: The amygdala receives direct inputs from the olfactory bulb, which bypasses the thalamus entirely. This explains why smells often trigger strong emotional memories and immediate reactions.

• Thalamus (Direct Pathway): The thalamus sends raw sensory information directly to the amygdala, bypassing detailed cortical processing. This pathway allows for rapid, reflexive responses to potentially threatening stimuli (e.g., a sudden loud noise or a fast-moving shadow).

• Sensory Cortex (Indirect Pathway): Sensory inputs from the thalamus are processed in detail by the primary sensory cortices (e.g., visual, auditory, or somatosensory cortices) before reaching the amygdala. This pathway allows for a slower, more accurate interpretation of stimuli.

Contextual Inputs

• Hippocampus: The hippocampus provides contextual information about the environment, such as where the stimulus occurred or the past experiences associated with it. This input is critical for associating emotions with specific memories.

• Prefrontal Cortex: The prefrontal cortex sends information about higher-order cognitive processing, such as goals, expectations, and decision-making. This input helps the amygdala evaluate the emotional relevance of stimuli within the context of current goals or intentions.

Regulatory Inputs

• Brainstem: The brainstem relays information about internal bodily states, such as heart rate, breathing, and pain signals. These inputs enable the amygdala to link autonomic responses with emotional stimuli.

• Hypothalamus: The hypothalamus sends signals related to stress, hormones, and homeostasis. These inputs allow the amygdala to adapt emotional responses based on physiological needs.

Outputs of the Amygdala

Hypothalamus - Autonomic

• The amygdala influences the autonomic nervous system (ANS) and hormonal secretion through its connections with the hypothalamus. It triggers physiological responses to emotional stimuli, such as increased heart rate, blood pressure, respiration, and stress hormone release (e.g., cortisol).

• Pathway for Emotions to Influence the Body: Emotional experiences, such as fear or anxiety, activate the hypothalamus, driving bodily responses through the ANS (e.g., fight-or-flight).

• Psychosomatic Phenomena: The close connection between emotions and bodily states explains psychosomatic effects, where emotional stress manifests as physical symptoms.

• Sudden Death: Extreme fear or stress can overstimulate the hypothalamus, leading to fatal cardiovascular events like sudden death syndrome.

Piriform Cortex - Olfaction

• The amygdala connects directly to the piriform cortex, the primary olfactory area, integrating olfactory information with emotions, enabling smells to evoke strong emotional responses and vivid memories.

• Pathway for Smell to Trigger Emotions: The close proximity of the amygdala and piriform cortex allows olfactory stimuli to directly influence emotional states.

• Uncinate Fits: In cases of medial temporal lobe epilepsy, seizures often begin with olfactory hallucinations (also called uncinate fits), reflecting the amygdala’s role in processing smells.

• Unique Organisation of the Olfactory System: The olfactory system is unique because it has a monosynaptic connection to the cortex (piriform cortex), bypassing the thalamus. This direct link enhances the immediacy of smell-triggered emotions.

Neocortex - Cognition

• The amygdala sends outputs to the neocortex, including the hippocampus, prefrontal cortex (PFC), and sensory cortices, integrating emotional salience into cognitive processes and decision-making by emotional learning and memory tagging.

• Pathway for the Amygdala to Tag Memories: The amygdala assigns emotional significance to memories stored in the hippocampus and neocortex by tagging the memories.

• Unique Relationship with the Hippocampus: The amygdala works closely with the hippocampus to link emotional experiences with specific contexts or events, strengthening episodic memory.

• Anti-Correlational Relationship with the Prefrontal Cortex: The amygdala's emotion-driven responses often compete with the reason-driven regulation of the PFC. (Example: In high-stress situations, the amygdala's influence (e.g., fear or aggression) can override rational decision-making by the PFC, explaining the "fight or flight vs. reason" dynamic.)

Lesion

• Kluber-Bucy Syndrome: Rare neurological disorder caused by bilateral damage to the amygdala and surrounding medial temporal lobe structures. It is characterized by a range of symptoms, including emotional blunting, loss of fear, hypersexuality, hyperorality (exploring objects with the mouth), hyperphagia (compulsive eating), and visual agnosia (difficulty recognizing familiar objects or faces), reflecting the amygdalas role in regulating fear, aggression and social-emotional behaviour.

  • Emotional Blunting: Loss of fear and flattened affect (lack of emotional responsiveness).

  • Hypersexuality: Inappropriate sexual behaviour, often directed at unusual objects or individuals.

  • Oral Fixation: A tendency to explore objects with the mouth rather than hands.

  • Hyperphagia: Excessive eating, often without concern for the edibility of objects.

  • Impaired Social Behavior: Failure to recognize social and emotional cues, leading to inappropriate interactions.

• Obsessive Compulsive Disorder: mental health condition characterized by intrusive, distressing thoughts (obsessions) and repetitive behaviors or mental acts (compulsions) performed to reduce anxiety. It is associated with overactivation of the amygdala, particularly in response to aversive or distressing stimuli, and a dysregulated interaction between the amygdala and prefrontal cortex. This dysfunction leads to exaggerated emotional responses, impaired cognitive control, and maladaptive coping mechanisms.

  • Heightened Emotional Responses: Exaggerated emotional reactions to unpleasant stimuli, such as "nasty pictures" or distressing thoughts.

  • Compulsive Behaviors: Repetitive actions aimed at reducing anxiety caused by emotional triggers (e.g., compulsive handwashing to alleviate contamination fears).

  • Intrusive Thoughts: Persistent, distressing thoughts often associated with guilt, fear, or disgust.