Anxiety/Fear- Hippocampus and Amygdala Flashcards
Which area of the brain is established in playing a role in the formation and retrieval of memories?
One area of the brain that has a well established role in the formation and retrieval of memories is the hippocampus. Pioneering studies done on patient H.M who suffered from profound anterograde amnesia, due to surgical removal of his medial temporal lobe to treat his epilepsy, arguably gave the first proof that the hippocampus plays an essential role in memory; particularly episodic memory.
What is the difference between episodic and semantic memory?
Episodic memory is a type of declarative memory- different from procedural. Episodic memory was defined by Tulving in 1972 “as memory for personally experienced events set in a spatio-temporal context”. This contrasts from the other type of declarative memory known as semantic memory- which refers to general factual knowledge, which are independent of personal experience and the spatial- temporal context in which it was required.
Semantic memories may once have had a personal context, but now stand alone as simple knowledge. In other words semantic memory is thought to be derived from the episodic memory, as we learn new facts or concepts from our experiences. However with time there is a gradual transition from episodic to semantic memory, in which episodic memory reduces its sensitivity and association to particular events, so that the information can be generalized as semantic memory.
What key experiment gave proof that the hippocampus is involved in spatial memory?
The Morris water maze is one of the most widely used tasks in behavioral neuroscience for studying the psychological processes and neural mechanisms of spatial learning and memory. The basic task is very simple. Animals, usually rats or mice, are placed in a large circular pool of water and required to escape from water onto a hidden platform whose location can normally be identified only using spatial memory. There are no local cues indicating where theK platform is located. Morris et al 1982, found that rats with an intact hippocampus find the platform easily compared to rats with a hippocampal lesion. Furthermore Morris et al found that cortical lesions had no effect on finding the platform. As a result this experiment gave evidence that hippocampus must be involved in spatial memory.
It is thought that the task derives from place cells that are neurons found in the hippocampus, which stably represent self-location. As a result is thought to make up a cognitive map to which episodic memories are anchored to. (O’Keefe, 1976).
Apart from the Morris water maze, what other experiments show that the hippocampus is required for spatial memory?
Similarly, humans with hippocampal damage also show impaired spatial memory (Hartley et al 2007) and PET scans during human navigation in a VR show a correlation between accuracy (successfully reaching a goal) and activation of the right hippocampus (Maguire et al 1998). This confirms the belief that the hippocampus is involved in spatial memory for humans also.
Are the dorsal and ventral hippocampus equally involved in mediating spatial memory? What are the two views?
Most studies have been done on the dorsal section of the HPC as it is easier to access- as a result the ventral section has been less explored and could have some other functions.
There are two views:
- No real difference. It’s all space but with a gradient of scales along the D-V axis hence the ventral extent can appear to be non-spatial when animal is constrained to small areas of the environment (i.e large scale can be mistaken for ‘context’)
- vHPC and dHPC are different. dHPC is involved in spatial processing but vHPC has a pronounced role in processing anxiety
What evidence shows that the vHPC does represent space and is involved in spatial memory?
Kjelstrup et al., 2008 showed that the VHPC does have place fields but of a larger scale.
The results suggest that the place-cell map includes the entire hippocampus and that environments are represented in the hippocampus at a topographically graded but finite continuum of scales.
Hafting et al 2005, Brunel et al 2008, showed that there is a gradient of grid scales along the dorsal- ventral (D-V axis) of the medial entorhinal cortex (MEC); small at the dorsal end and large at the ventral end. As it is known that the MEC D-V maps directly onto the HPC D-V axis it implies the ventral HPC is a large scale space also.
Further evidence supporting that the vHPC does represent space at a larger scale is work done by Evensmoen et al. 2013.
In this study, participants learned a virtual environment and then had to find their way during fMRI. He found that the activation in the hippocampal head (vHPC) was associated with multiple distance and global direction judgments and to the use of a coarse, global environmental representation during navigation. Activation in the hippocampal tail (dHPC) however was associated with fine- grained local representations and navigation strategies, such as number of turns on a route.
Evidence that vHPC does not represent space or at least is less spatial than dHPC?
Moser et al 1993, showed that damage to the ventral HPC largely spares spatial information on Morris Water Maze, whereas even small dorsal HPC lesions have a a pronounced effect on escape latency in MWM (rat slow to find platform)- however many people say that you may get same result for vHPC if a MWM was at a larger scale
Maguire et al 2000 showed that in London taxi drivers there posterior HPC is enlarged but not their anterior and that their pHPC appears to enlarge with continued experience. This supports the view that the DHPC encodes space and the vHPC less so.
There are also anatomical reasons which support the idea that the vHPC is dis tin the from the dHPC- the vHPC has strong reciprocal connectivity with the amygdala which is associated with emotional processing specifically fear and anxiety . The vHPC also projects to the prefrontal cortex- dHPC less so.
Similarly, molecular markers differ along the D-V axis of the hippocampus also. In rodents number of calretinin-immunoreactive mossy cells is larger in vHPC than dHPC. Also, the density of dopaminergic, noradrenergic & serotonergic terminals is larger in vHPC, suggesting different functions.
Why vHPC representing space and its role in anxiety are not mutually exclusive ideas?
The increasing representation of space along the dorsoventral axis of the parahippocampal spatial system may very well reflect an axis of generalization. With increased scale of spatial fields in the hippocampus and the MEC, the larger fields do not denote spatial location with equal demarcation, resulting in diminished spatial resolution. In other words, aparticular point in space will result in a greater proportion of active place cells in the vHPC, compared to the dHPC, so coding of a location becomes more generalised.
This generalisation makes it easier to associate a space or a memory to a context. As the ventral hippocampus is known to be more associated with stress and fear response due to stronger connections with the amygdala (Moser and Moser 1998). For embedding fear memories into spatial context, this generalisation may be advantageous.
Does vHPC have a specific role in processing fear and/or anxiety or can it just do that because it represents space on a larger scale?
Not a specific role- Fear conditioning in rodents result in protective immobility in response to a conditioned stimuli- Richmond et al 1999 found that a dHPC lesion had little to no effect on the expression of the contextual fear condition (freezing) but vHPC had a large effect
Problem with this test is that fear conditioning requires learning in the first place and therefore the hippocampus. Furthermore some people believe the difference in effect between v and d lesions could just be that vHPC have larger place fields that are associated with context.
Specific role as experiment didn’t involve context-
Bannerman et al 2002 found that in rats with vHPC lesions appeared to have reduced anxiety as they were quicker to enter anxiogenic environments such as, the elevated plus maze. These rats had increased social interaction and reduced hyponeophagia. Hyponeophagia- the phenomenon in which exposure to a novel environment suppresses feeding behavior- can be used as an anxiety assessment in animals. Contrastingly, he found that also found that rats with dHPC lesions did not produce these effects.
He also found that dHPC resulted in the rats becoming hyperactive- it is unclear why- is this an anxiety effect?
This experiment proves that vHPC has a specific role in anxiety as using elevated plus maze didn’t require learning and therefore use of the hippocampus, specifically the vHPC’s role in associating a location with a fearful context.
Evidence that shows that vHPC is functionally distinct from the amygdala?
Surprisingly lesions to amygdala produce different effects to vHPC lesions:
The Successive alleys test is a novel anxiety test that utilizes fear of open spaces as an assay. Amygdala lesions have no effects on the successive alley test nor elevated plus maze.
Amygdala lesion reduce effects of benzodiazepine on plus maze and reduce social interaction as oppose to increase like we see in vHPC lesions. Furthermore, amygdala lesions result in increased hyponeogphagia.
As a result, it is thought they have functionally distinct roles; vHPC has role in processing anxiety & amygdala in fear
Define fear and anxiety. What is the difference between them?
Gray and McNaughton 2003 and Davis et al 1999 defined fear as a physical response to explicit conditions and cues- as it result it tends to be intense and short lived. However anxiety is a tonic response to diffuse, often unconditioned, aversive cues or situations. As a result it is prolonged and moderate.
Sometimes a fearful response can lead to anxiety that comes on when introduced to a similar context.
Ethologists define fear as a motivational state aroused by specific stimuli that give rise to defensive behavior or escape. Anxiety is a generalized response to an unknown threat or internal conflict, whereas fear is focused on known external danger.
What evidence is there that amygdala has a role in processing fear?
Studies of Pavlovian fear conditioning in non-humans have highlighted the importance of the amygdala in the acquisition of fear conditioning (LeDoux, 2000). Similarly, functional neuroimaging studies in humans have reported amygdala activation during fear conditioning (Alvarez et al, 2008).In addition, amygdala activity has been associated with skin conductance changes during fear conditioning (Cheng et al, 2006).
Interestingly, amygdala activation in humans also has been observed in response to cues following (1) verbal instructions that discriminate between cues that predict shock vs safety (even though no shock was actually administered) (Phelps et al, 2001), and (2) observational fear learning, whereby participants watch a video of another person experiencing a Pavlovian fear-conditioning paradigm (Olsson et al, 2007). What exactly amygdaloid activation represents in these latter paradigms is not entirely clear. It could suggest for example that: (1) higher order centers that decipher the anticipated predictive value of the cue, or that learn from observation using empathy, convey information to the amygdala, or (2) alternatively, that the human amygdala is less specific in its responses and is more sensitive to contextual modulation in the absence of a US. These interpretations could have potentially different implications for the understanding of the role of the amygdala in anxiety disorders.
What evidence is there that the amygdala does in fact have a role in anxiety?
Several studies have reported increased amygdala activation in PTSD relative to comparison groups in response to trauma-related imagery (Shin et al, 2004). Exaggerated amygdala activation in PTSD has also been found at rest (Chung et al, 2006).Several studies, however, have found no differential response in the amygdala in PTSD (eg, Bremner et al, 1999).
What does damage to the lateral nucleus of the amygdala result in?
It is well established that the amygdala plays an essential role in Pavlovian fear conditioning, with the lateral nucleus serving as the interface with sensory systems that transmit the conditioned stimulus and the central nucleus as the link with motor regions that control conditioned fear responses. The lateral nucleus connects with the central nucleus directly and by way of several other amygdala regions, including the basal, accessory basal, and medial nuclei. (Le Doux, 2000)
The fact that damage to B, AB, B, and AB together or M fail to interfere with fear conditioning strongly suggests that LA and CE are sufficient on their own. Two interpretations follow from these findings. First, the direct connections from LA to CE, rather than indirect pathways involving the other nuclei, are necessary for fear conditioning. Second, information from the LA can use redundant indirect routes to the CE to engage the freezing response. For example, the B may normally link the LA and CE. However, in its absence, projections from the LA to the CE may substitute.
What does damage to basolateral nucelus of the amygadala result in?
The main projections of the hippocampus terminate in the basolateral nucelus (Canteras and Swanson, 1992) and as the hippocampus is involved in contextual fear conditioning, lesions of the basolateral nucleus will impair contextual fear conditioning.
